Cyclooxygenase-2 selective inhibitors, compositions and methods of use

ABSTRACT

The invention describes novel cyclooxygenase 2 (COX-2) selective inhibitors and novel compositions comprising at least one cyclooxygenase 2 (COX-2) selective inhibitor, and, optionally, at least one compound that donates, transfers or releases nitric oxide, stimulates endogenous synthesis of nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor or is a substrate for nitric oxide synthase, and/or at least one therapeutic agent. The invention also provides novel kits comprising at least one COX-2 selective inhibitor, optionally nitrosated and/or nitrosylated, and, optionally, at least one nitric oxide donor, and/or, optionally, at least one therapeutic agent. The novel cyclooxygenase 2 selective inhibitors of the invention can be optionally nitrosated and/or nitrosylated. The invention also provides methods for treating inflammation, pain and fever; for treating and/or improving the gastrointestinal properties of COX-2 selective inhibitors; for facilitating wound healing; for treating and/or preventing renal and/or respiratory toxicity; for treating and/or preventing other disorders resulting from elevated levels of cyclooxygenase-2; and for improving the cardiovascular profile of COX-2 selective inhibitors.

RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.11/418,187, filed May 5, 2006, now allowed, which is a divisional ofU.S. application Ser. No. 10/603,098, filed Jun. 25, 2003, issued asU.S. Pat. No. 7,087,630, which claims priority under 35 USC § 119 toU.S. Application No. 60/391,769 filed Jun. 27, 2002, and U.S.Application No. 60/454,307 filed Mar. 14, 2003.

FIELD OF THE INVENTION

The invention describes novel nitrosated and/or nitrosylatedcyclooxygenase 2 (COX-2) selective inhibitors and novel compositionscomprising at least one nitrosated and/or nitrosylated cyclooxygenase 2(COX-2) selective inhibitor, and, optionally, at least one compound thatdonates, transfers or releases nitric oxide, stimulates endogenoussynthesis of nitric oxide, elevates endogenous levels ofendothelium-derived relaxing factor or is a substrate for nitric oxidesynthase, and/or at least one therapeutic agent. The invention alsoprovides novel compositions comprising at least one COX-2 selectiveinhibitor, that is optionally nitrosated and/or nitrosylated, and atleast one compound that donates, transfers or releases nitric oxide,elevates endogenous levels of endothelium-derived relaxing factor,stimulates endogenous synthesis of nitric oxide or is a substrate fornitric oxide synthase and/or at least one therapeutic agent. Theinvention also provides novel kits comprising at least one COX-2selective inhibitor, that is optionally nitrosated and/or nitrosylated,and, optionally, at least one nitric oxide donor and/or at least onetherapeutic agent. The invention also provides methods for treatinginflammation, pain and fever; for treating gastrointestinal disordersand/or improving the gastrointestinal properties of COX-2 selectiveinhibitors; for facilitating wound healing; for treating and/orpreventing renal and/or respiratory toxicities; for treating and/orpreventing other disorders resulting from elevated levels ofcyclooxygenase-2; and for improving the cardiovascular profile of COX-2selective inhibitors.

BACKGROUND OF THE INVENTION

Nonsteroidal anti-inflammatory compounds (NSAIDs) are widely used forthe treatment of pain, inflammation, and acute and chronic inflammatorydisorders such as osteoarthritis and rheumatoid arthritis. Thesecompounds inhibit the activity of the enzyme cyclooxygenase (COX), alsoknown as prostaglandin G/H synthase, which is the enzyme that convertsarachidonic acid into prostanoids. The NSAIDs also inhibit theproduction of other prostaglandins, especially prostaglandin G₂,prostaglandin H₂ and prostaglandin E₂, thereby reducing theprostaglandin-induced pain and swelling associated with the inflammationprocess. The chronic use of NSAIDs has been associated with adverseeffects, such as gastrointestinal ulceration and renal toxicity. Theundesirable side effects are also due to the inhibition of prostaglandinin the affected organ.

Recently two isoforms of cyclooxygenase, encoded by two distinct genes(Kujubu et al, J. Biol. Chem., 266, 12866-12872 (1991)), have beenidentified—a constitutive form, cyclooxygenase-1 (COX-1), and aninductive form, cyclooxygenase-2 (COX-2). It is thought that theantiinflammatory effects of NSAIDs are mediated by the inhibition ofCOX-2, whereas the side effects seem to be caused by the inhibition ofCOX-1. The NSAIDs currently on the market either inhibit both isoformsof COX with little selectivity for either isoform or are COX-1selective. Recently compounds that are COX-2 selective inhibitors havebeen developed and marketed. These COX-2 selective inhibitors have thedesired therapeutic profile of an antiinflammatory drug without theadverse effects commonly associated with the inhibition of COX-1.However, these compounds can result in dyspepsia and can causegastropathy (Mohammed et al, N. Engl. J. Med., 340(25) 2005 (1999)).Additionally the COX-2 selective inhibitors can increase the risk ofcardiovascular events in a patient (Mukherjee et al., JAMA 286(8)954-959 (2001)); Hennan et al., Circulation, 104:820-825 (2001)).

There is still a need in the art for novel COX-2 selective inhibitorcompounds that have gastroprotective properties, facilitate woundhealing, decreased renal toxicity and dyspepsia, improved cardiovascularprofile and that can be used at low dosages. The invention is directedto these, as well as other, important ends.

SUMMARY OF THE INVENTION

The invention provides novel COX-2 selective inhibitors, or apharmaceutically acceptable salt thereof. These compounds are potentanalgesics, have antiinflammatory properties and have an unexpectedpotential for facilitating wound healing. The novel compounds also haveunexpected properties in the treatment and/or prevention of renal and/orrespiratory toxicity and for improving the cardiovascular profile ofCOX-2 selective inhibitors. The COX-2 selective inhibitor, or apharmaceutically acceptable salt thereof, can be nitrosated and/ornitrosylated through one or more sites, such as oxygen (hydroxylcondensation), sulfur (sulfhydryl condensation) and/or nitrogen. Theinvention also provides compositions comprising the novel compoundsdescribed herein in a pharmaceutically acceptable carrier.

The invention is also based on the discovery that administering at leastone COX-2 selective inhibitor and at least one nitric oxide donor oradministering at least one nitrosated and/or nitrosylated COX-2selective inhibitor, and, optionally, at least one nitric oxide donorreduces the gastrointestinal toxicity induced by COX-2 selectiveinhibitors. Nitric oxide donors include, for example, S-nitrosothiols,nitrites, nitrates, N-oxo-N-nitrosamines, SPM 3672, SPM 5185, SPM 5186and analogues thereof, and substrates of the various isozymes of nitricoxide synthase. Thus, another aspect of the invention providescompositions comprising at least one COX-2 selective inhibitor, that isoptionally substituted with at least one NO and/or NO₂ group (i.e.,nitrosylated and/or nitrosated), and at least one compound that donates,transfers or releases nitric oxide as a charged species, i.e.,nitrosonium (NO⁺) or nitroxyl (NO⁻), or as the neutral species, nitricoxide (NO.), and/or stimulates endogenous production of nitric oxide orEDRF in vivo and/or is a substrate for nitric oxide synthase. Theinvention also provides for such compositions in a pharmaceuticallyacceptable carrier.

Yet another aspect of the invention provides compositions comprising atleast one COX-2 selective inhibitor, that is optionally substituted withat least one NO₂ group and/or at least one NO group (i.e., nitrosatedand/or nitrosylated respectively), and, optionally, at least onecompound that donates, transfers or releases nitric oxide as a chargedspecies, i.e., nitrosonium (NO⁺) or nitroxyl (NO⁻), or as the neutralspecies, nitric oxide (NO.), and/or stimulates endogenous production ofnitric oxide or EDRF in vivo and/or is a substrate for nitric oxidesynthase, and/or, optionally, at least one therapeutic agent, includingbut not limited to, steroids, nonsteroidal antiinflammatory compounds(NSAID), 5-lipoxygenase (5-LO) inhibitors, leukotriene B₄ (LTB₄)receptor antagonists, leukotriene A₄ (LTA₄) hydrolase inhibitors, 5-HTagonists, HMG CoA inhibitors, H₂ antagonists, antineoplastic agents,antiplatelet agents, thrombin inhibitors, thromboxane inhibitors,decongestants, diuretics, sedating or non-sedating anti-histamines,inducible nitric oxide synthase inhibitors, opioids, analgesics,Helicobacter pylori inhibitors, proton pump inhibitors, isoprostaneinhibitors, and the like. The invention also provides for suchcompositions in a pharmaceutically acceptable carrier.

Yet another aspect of the present invention provides methods fortreating and/or preventing inflammation, pain and fever; for treatinggastrointestinal disorders and/or improving gastrointestinal propertiesof COX-2 inhibitors; for facilitating wound healing; for treating and/orpreventing renal and/or respiratory toxicity; and for treating and/orpreventing COX-2 mediated disorders (i.e., disorders resulting fromelevated levels of COX-2) in a patient in need thereof which comprisesadministering to the patient a therapeutically effective amount of atleast one COX-2 selective inhibitor, that is optionally substituted withat least one NO₂ group and/or at least one NO group (i.e., nitrosatedand/or nitrosylated respectively), and, optionally, at least onecompound that donates, transfers or releases nitric oxide as a chargedspecies, i.e., nitrosonium (NO⁺) or nitroxyl (NO⁻), or as the neutralspecies, nitric oxide (NO.), and/or stimulates endogenous production ofnitric oxide or EDRF in vivo and/or is a substrate for nitric oxidesynthase and/or stimulates endogenous production of NO or EDRF in vivoand/or is a substrate for nitric oxide synthase (i.e., NO donors). Themethods can optionally further comprise the administration of at leastone therapeutic agent, such as, for example, steroids, nonsteroidalantiinflammatory compounds (NSAID), 5-lipoxygenase (5-LO) inhibitors,leukotriene B₄ (LTB₄) receptor antagonists, leukotriene A₄ (LTA₄)hydrolase inhibitors, 5-HT agonists, HMG CoA inhibitors, H₂ antagonists,antineoplastic agents, antiplatelet agents, thrombin inhibitors,thromboxane inhibitors, decongestants, diuretics, sedating ornon-sedating anti-histamines, inducible nitric oxide synthaseinhibitors, opioids, analgesics, Helicobacter pylori inhibitors, protonpump inhibitors, isoprostane inhibitors, and mixtures of two or morethereof. In this aspect of the invention, the methods can involveadministering the COX-2 selective inhibitors, that are optionallynitrosated and/or nitrosyalted, administering the COX-2 selectiveinhibitors, that are optionally nitrosated and/or nitrosylated and NOdonors, administering the COX-2 selective inhibitors, that areoptionally nitrosated and/or nitrosylated, and therapeutic agents, oradministering the COX-2 selective inhibitors, that are optionallynitrosated and/or nitrosylated, NO donors and therapeutic agents. Theselective COX-2 inhibitors, nitric oxide donors, and/or therapeuticagents can be administered separately or as components of the samecomposition in one or more pharmaceutically acceptable carriers.

Yet another aspect of the invention provides methods for improving thecardiovascular profile of COX-2 selective inhibitors in a patient inneed thereof which comprises administering to the patient atherapeutically effective amount of at least one COX-2 selectiveinhibitor, optionally substituted with at least one NO₂ and/or NO group(i.e. nitrosated and/or nitrosylated), and, optionally, at least onecompound that donates, transfers or releases nitric oxide as a chargedspecies, i.e., nitrosonium (NO⁺) or nitroxyl (NO⁻), or as the neutralspecies, nitric oxide (NO.), and/or stimulates endogenous production ofnitric oxide or EDRF in vivo and/or is a substrate for nitric oxidesynthase and/or stimulates endogenous production of NO or EDRF in vivoand/or is a substrate for nitric oxide synthase (i.e. NO donor). Themethods can optionally further comprise the administration of at leastone of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors,antiplatelet agents, thrombin inhibitors, thromboxane inhibitors, andmixtures of two or more thereof. In this aspect of the invention, themethods can involve administering the nitrosated and/or nitrosylatedCOX-2 selective inhibitors, administering the COX-2 selectiveinhibitors, that are optionally nitrosated and/or nitrosylated, and NOdonors, administering the COX-2 selective inhibitors, that areoptionally nitrosated and/or nitrosylated, and at least one of3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors, antiplateletagents, thrombin inhibitors or thromboxane inhibitors, or administeringthe COX-2 selective inhibitors, that are optionally nitrosated and/ornitrosylated, NO donors, and at least one of 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) inhibitors, antiplatelet agents, thrombininhibitors or thromboxane inhibitors. The COX-2 inhibitors, nitric oxidedonors, and/or 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)inhibitors, antiplatelet agents, thrombin inhibitors or thromboxaneinhibitors can be administered separately or as components of the samecomposition in one or more pharmaceutically acceptable carriers.

In yet another aspect the invention provides kits comprising at leastone COX-2 selective inhibitor, that is optionally substituted with atleast one NO₂ group and/or at least one NO group (i.e., nitrosatedand/or nitrosylated respectively), and, optionally, at least onecompound that donates, transfers or releases nitric oxide as a chargedspecies, i.e., nitrosonium (NO⁺) or nitroxyl (NO⁻), or as the neutralspecies, nitric oxide (NO.), and/or stimulates endogenous production ofnitric oxide or EDRF in vivo and/or is a substrate for nitric oxidesynthase. The kit can further comprise at least one therapeutic agent,such as, for example, steroids, nonsteroidal antiinflammatory compounds(NSAID), 5-lipoxygenase (5-LO) inhibitors, leukotriene B₄ (LTB₄)receptor antagonists, leukotriene A₄ (LTA₄) hydrolase inhibitors, 5-HTagonists, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors, H₂antagonists, antineoplastic agents, antiplatelet agents, thrombininhibitors, thromboxane inhibitors, decongestants, diuretics, sedatingor non-sedating anti-histamines, inducible nitric oxide synthaseinhibitors, opioids, analgesics, Helicobacter pylori inhibitors, protonpump inhibitors, isoprostane inhibitors, and mixtures of two or morethereof. The COX-2 selective inhibitor, the nitric oxide donor and/ortherapeutic agent, can be separate components in the kit or can be inthe form of a composition in the kit in one or more pharmaceuticallyacceptable carriers.

DETAILED DESCRIPTION OF THE INVENTION

As used throughout the disclosure, the following terms, unless otherwiseindicated, shall be understood to have the following meanings.

“NSAID” refers to a nonsteroidal anti-inflammatory compound or anonsteroidal anti-inflammatory drug. NSAIDs inhibit cyclooxygenase, theenzyme responsible for the biosyntheses of the prostaglandins andcertain autocoid inhibitors, including inhibitors of the variousisozymes of cyclooxygenase (including but not limited tocyclooxygenase-1 and -2), and as inhibitors of both cyclooxygenase andlipoxygenase.

“Cyclooxygenase-2 (COX-2) selective inhibitor” refers to a compound thatselectively inhibits the cyclooxygenase-2 enzyme over thecyclooxygenase-1 enzyme. In one embodiment, the compound has acyclooxygenase-2 IC₅₀ of less than about 2 μM and a cyclooxygenase-1IC₅₀ of greater than about 5 μM, in the human whole blood COX-2 assay(as described in Brideau et al., Inflamm Res., 45: 68-74 (1996)) andalso has a selectivity ratio of cyclooxygenase-2 inhibition overcyclooxygenase-1 inhibition of at least 10, and preferably of at least40. In another embodiment, the compound has a cyclooxygenase-1 IC₅₀ ofgreater than about 1 μM, and preferably of greater than 20 μM. Thecompound can also inhibit the enzyme, lipoxygenase. Such selectivity mayindicate an ability to reduce the incidence of common NSAID-induced sideeffects.

“Parent COX-2 inhibitor” refers to a non-nitrosated and/ornon-nitrosylated COX-2 inhibitor, or pharmaceutically acceptable saltsthereof or pharmaceutically acceptable esters thereof. “Parent COX-2inhibitor” includes the compounds of Formulas (I), (II) and (III) beforethey are nitrosated and/or nitrosylated by the methods described herein.

“Therapeutic agent” includes any therapeutic agent that can be used totreat or prevent the diseases described herein. “Therapeutic agents”include, for example, steroids, nonsteroidal antiinflammatory compounds,5-lipoxygenase inhibitors, leukotriene B₄ receptor antagonists,leukotriene A₄ hydrolase inhibitors, 3-hydroxy-3-methylglutaryl coenzymeA inhibitors, H₂ antagonists, antineoplastic agents, antiplateletagents, thrombin inhibitors, thromboxane inhibitors, decongestants,diuretics, sedating or non-sedating anti-histamines, inducible nitricoxide synthase inhibitors, opioids, analgesics, Helicobacter pyloriinhibitors, proton pump inhibitors, isoprostane inhibitors, and thelike. Therapeutic agent includes the pro-drugs and pharmaceuticalderivatives thereof including but not limited to the correspondingnitrosated and/or nitrosylated derivatives. Although nitric oxide donorshave therapeutic activity, the term “therapeutic agent” does not includethe nitric oxide donors described herein, since nitric oxide donors areseparately defined.

“Cardiovascular disease or disorder” refers to any cardiovasculardisease or disorder known in the art, including, but not limited to,restenosis, atherosclerosis, atherogenesis, angina, (particularlychronic, stable angina pectoris), ischemic disease, congestive heartfailure or pulmonary edema associated with acute myocardial infarction,thrombosis, controlling blood pressure in hypertension (especiallyhypertension associated with cardiovascular surgical procedures),thromboembolic events, platelet aggregation, platelet adhesion, smoothmuscle cell proliferation, vascular complications associated with theuse of medical devices, wounds associated with the use of medicaldevices, cerebrovascular ischemic events, and the like. Complicationsassociated with the use of medical devices may occur as a result ofincreased platelet deposition, activation, thrombus formation orconsumption of platelets and coagulation proteins. Such complications,which are within the definition of “cardiovascular disease or disorder,”include, for example, myocardial infarction, ischemic stroke, transientischemic stroke, thromboembolic events, pulmonary thromboembolism,cerebral thromboembolism, thrombophlebitis, thrombocytopenia, bleedingdisorders and/or any other complications which occur either directly orindirectly as a result of the foregoing disorders.

“Restenosis” is a cardiovascular disease or disorder that refers to theclosure of a peripheral or coronary artery following trauma to theartery caused by an injury such as, for example, angioplasty, balloondilation, atherectomy, laser ablation treatment or stent insertion.Restenosis can also occur following a number of invasive surgicaltechniques, such as, for example, transplant surgery, vein grafting,coronary artery bypass surgery, endarterectomy, heart transplantation,balloon angioplasty, atherectomy, laser ablation, endovascular stenting,and the like.

“Atherosclerosis” is a form of chronic vascular injury in which some ofthe normal vascular smooth muscle cells in the artery wall, whichordinarily control vascular tone regulating blood flow, change theirnature and develop “cancer-like” behavior. These vascular smooth musclecells become abnormally proliferative, secreting substances such asgrowth factors, tissue-degradation enzymes and other proteins, whichenable them to invade and spread into the inner vessel lining, blockingblood flow and making that vessel abnormally susceptible to beingcompletely blocked by local blood clotting, resulting in the death ofthe tissue served by that artery. Atherosclerotic cardiovasculardisease, coronary heart disease (also known as coronary artery diseaseor ischemic heart disease), cerebrovascular disease and peripheralvessel disease are all common manifestations of atherosclerosis and aretherefore encompassed by the terms “atherosclerosis” and“atherosclerotic disease”.

“Improving the cardiovascular profile” refers to and includes reducingthe risk of like events, reducing the risk of developing atherosclerosisand atherosclerotic diseases, and inhibiting platelet aggregation of theparent COX-2 inhibitor.

“Thromboembolic events” includes, but is not limited to, ischemicstroke, transient ischemic stroke, myocardial infarction, anginapectoris, thrombosis, thromboembolism, thrombotic occlusion andreocclusion, acute vascular events, restenosis, transient ischemicattacks, and first and subsequent thrombotic stroke. Patients who are atrisk of developing thromboembolic events, may include those with afamilial history of, or genetically predisposed to, thromboembolicdisorders, who have had ischemic stroke, transient ischemic stroke,myocardial infarction, and those with unstable angina pectoris orchronic stable angina pectoris and patients with alteredprostacyclin/thromboxane A₂ homeostasis or higher than normalthromboxane A₂ levels leading to increase risk for thromboembolism,including patients with diabetes and rheumatoid arthritis.

“Thromboxane inhibitor” refers to any compound that reversibly orirreversibly inhibits thromboxane synthesis, and includes compoundswhich are the so-called thromboxane A₂ receptor antagonists, thromboxaneA₂ antagonists, thromboxane A₂/prostaglandin endoperoxide antagonists,thromboxane receptor (TP) antagonists, thromboxane antagonists,thromboxane synthase inhibitors, and dual acting thromboxane synthaseinhibitors and thromboxane receptor antagonists. The characteristics ofthe preferred thromboxane inhibitor should include the suppression ofthromboxane A₂ formation (thromboxane synthase inhibitors) and/orblockade of thromboxane A₂ and prostaglandin H₂ platelet and vessel wall(thromboxane receptor antagonists). The effects should block plateletactivation and therefore platelet function.

“Thromboxane A₂ receptor antagonist” refers to any compound thatreversibly or irreversibly blocks the activation of any thromboxane A₂receptor.

“Thromboxane synthase inhibitor” refers to any compound that reversiblyor irreversibly inhibits the enzyme thromboxane synthesis therebyreducing the formation of thromboxane A₂. Thromboxane synthaseinhibitors may also increase the synthesis of antiaggregatoryprostaglandins including prostacyclin and prostaglandin D₂. ThromboxaneA₂ receptor antagonists and thromboxane synthase inhibitors and can beidentified using the assays described in Tai, Methods of Enzymology,Vol. 86, 110-113 (1982); Hall, Medicinal Research Reviews, 11:503-579(1991) and Coleman et al., Pharmacol Rev., 46: 205-229 (1994) andreferences therein, the disclosures of which are incorporated herein byreference in its entirety.

“Dual acting thromboxane receptor antagonist and thromboxane synthaseinhibitor” refers to any compound that simultaneously acts as athromboxane A₂ receptor antagonist and a thromboxane synthase inhibitor.

“Thrombin inhibitors” refers to and includes compounds that inhibithydrolytic activity of thrombin, including the catalytic conversion offibrinogen to fibrin, activation of Factor V to Va, Factor VIII toVIIIa, Factor XIII to XIIIa and platelet activation. Thrombin inhibitorsmay be identified using assays described in Lewis et al., ThrombosisResearch. 70: 173-190 (1993).

“Platelet aggregation” refers to the binding of one or more platelets toeach other. Platelet aggregation is commonly referred to in the contextof generalized atherosclerosis, not with respect to platelet adhesion onvasculature damaged as a result of physical injury during a medicalprocedure. Platelet aggregation requires platelet activation whichdepends on the interaction between the ligand and its specific plateletsurface receptor.

“Platelet activation” refers either to the change in conformation(shape) of a cell, expression of cell surface proteins (e.g., theIIb/IIIa receptor complex, loss of GPIb surface protein), and secretionof platelet derived factors (e.g., serotonin, growth factors).

“Patient” refers to animals, preferably mammals, most preferably humans,and includes males and females, and children and adults.

“Therapeutically effective amount” refers to the amount of the compoundand/or composition that is effective to achieve its intended purpose.

“Transdermal” refers to the delivery of a compound by passage throughthe skin and into the blood stream.

“Transmucosal” refers to delivery of a compound by passage of thecompound through the mucosal tissue and into the blood stream.

“Penetration enhancement” or “permeation enhancement” refers to anincrease in the permeability of the skin or mucosal tissue to a selectedpharmacologically active compound such that the rate at which thecompound permeates through the skin or mucosal tissue is increased.

“Carriers” or “vehicles” refers to carrier materials suitable forcompound administration and include any such material known in the artsuch as, for example, any liquid, gel, solvent, liquid diluent,solubilizer, or the like, which is non-toxic and which does not interactwith any components of the composition in a deleterious manner.

“Nitric oxide adduct” or “NO adduct” refers to compounds and functionalgroups which, under physiological conditions, can donate, release and/ordirectly or indirectly transfer any of the three redox forms of nitrogenmonoxide (NO⁺, NO⁻, NO.), such that the biological activity of thenitrogen monoxide species is expressed at the intended site of action.

“Nitric oxide releasing” or “nitric oxide donating” refers to methods ofdonating, releasing and/or directly or indirectly transferring any ofthe three redox forms of nitrogen monoxide (NO⁺, NO⁻, NO.), such thatthe biological activity of the nitrogen monoxide species is expressed atthe intended site of action.

“Nitric oxide donor” or “NO donor” refers to compounds that donate,release and/or directly or indirectly transfer a nitrogen monoxidespecies, and/or stimulate the endogenous production of nitric oxide orendothelium-derived relaxing factor (EDRF) in vivo and/or elevateendogenous levels of nitric oxide or EDRF in vivo. “NO donor” alsoincludes compounds that are substrates for nitric oxide synthase.

“Alkyl” refers to a lower alkyl group, a haloalkyl group, a hydroxyalkylgroup, an alkenyl group, an alkynyl group, a bridged cycloalkyl group, acycloalkyl group or a heterocyclic ring, as defined herein. An alkylgroup may also comprise one or more radical species, such as, forexample a cycloalkylalkyl group or a heterocyclicalkyl group.

“Lower alkyl” refers to branched or straight chain acyclic alkyl groupcomprising one to about ten carbon atoms (preferably one to about eightcarbon atoms, more preferably one to about six carbon atoms). Exemplarylower alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, t-butyl, pentyl, neopentyl, iso-amyl, hexyl, octyl,and the like.

“Substituted lower alkyl” refers to a lower alkyl group, as definedherein, wherein one or more of the hydrogen atoms have been replacedwith one or more R¹⁰⁰ groups, wherein each R¹⁰⁰ is independently ahydroxy, an oxo, a carboxyl, a carboxamido, a halo, a cyano or an aminogroup, as defined herein.

“Haloalkyl” refers to a lower alkyl group, an alkenyl group, an alkynylgroup, a bridged cycloalkyl group, a cycloalkyl group or a heterocyclicring, as defined herein, to which is appended one or more halogens, asdefined herein. Exemplary haloalkyl groups include trifluoromethyl,chloromethyl, 2-bromobutyl, 1-bromo-2-chloro-pentyl, and the like.

“Alkenyl” refers to a branched or straight chain C₂-C₁₀ hydrocarbon(preferably a C₂-C₈ hydrocarbon, more preferably a C₂-C₆ hydrocarbon)that can comprise one or more carbon-carbon double bonds. Exemplaryalkenyl groups include propylenyl, buten-1-yl, isobutenyl, penten-1-yl,2,2-methylbuten-1-yl, 3-methylbuten-1-yl, hexan-1-yl, hepten-1-yl,octen-1-yl, and the like.

“Lower alkenyl” refers to a branched or straight chain C₂-C₄ hydrocarbonthat can comprise one or two carbon-carbon double bonds.

“Substituted alkenyl” refers to a branched or straight chain C₂-C₁₀hydrocarbon (preferably a C₂-C₈ hydrocarbon, more preferably a C₂-C₆hydrocarbon) which can comprise one or more carbon-carbon double bonds,wherein one or more of the hydrogen atoms have been replaced with one ormore R¹⁰⁰ groups, wherein each R¹⁰⁰ is independently a hydroxy, an oxo,a carboxyl, a carboxamido, a halo, a cyano or an amino group, as definedherein.

“Alkynyl” refers to an unsaturated acyclic C₂-C₁₀ hydrocarbon(preferably a C₂-C₈ hydrocarbon, more preferably a C₂-C₆ hydrocarbon)that can comprise one or more carbon-carbon triple bonds. Exemplaryalkynyl groups include ethynyl, propynyl, butyn-1-yl, butyn-2-yl,pentyl-1-yl, pentyl-2-yl, 3-methylbutyn-1-yl, hexyl-1-yl, hexyl-2-yl,hexyl-3-yl, 3,3-dimethyl-butyn-1-yl, and the like.

“Bridged cycloalkyl” refers to two or more cycloalkyl groups,heterocyclic groups, or a combination thereof fused via adjacent ornon-adjacent atoms. Bridged cycloalkyl groups can be unsubstituted orsubstituted with one, two or three substituents independently selectedfrom alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo,carboxyl, alkylcarboxylic acid, aryl, amidyl, ester, alkylcarboxylicester, carboxamido, alkylcarboxamido, oxo and nitro. Exemplary bridgedcycloalkyl groups include adamantyl, decahydronapthyl, quinuclidyl,2,6-dioxabicyclo(3.3.0)octane, 7-oxabycyclo(2.2.1)heptyl,8-azabicyclo(3,2,1)oct-2-enyl and the like.

“Cycloalkyl” refers to a saturated or unsaturated cyclic hydrocarboncomprising from about 3 to about 10 carbon atoms. Cycloalkyl groups canbe unsubstituted or substituted with one, two or three substituentsindependently selected from alkyl, alkoxy, amino, alkylamino,dialkylamino, arylamino, diarylamino, alkylarylamino, aryl, amidyl,ester, hydroxy, halo, carboxyl, alkylcarboxylic acid, alkylcarboxylicester, carboxamido, alkylcarboxamido, oxo, alkylsulfinyl, and nitro.Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclohexenyl, cyclohepta-1,3-dienyl, and thelike.

“Heterocyclic ring or group” refers to a saturated or unsaturated cyclichydrocarbon group having about 2 to about 10 carbon atoms (preferablyabout 4 to about 6 carbon atoms) where 1 to about 4 carbon atoms arereplaced by one or more nitrogen, oxygen and/or sulfur atoms. Sulfurmaybe in the thio, sulfinyl or sulfonyl oxidation state. Theheterocyclic ring or group can be fused to an aromatic hydrocarbongroup. Heterocyclic groups can be unsubstituted or substituted with one,two or three substituents independently selected from alkyl, alkoxy,amino, alkylthio, aryloxy, arylthio, arylalkyl, hydroxy, oxo, thial,halo, carboxyl, carboxylic ester, alkylcarboxylic acid, alkylcarboxylicester, aryl, arylcarboxylic acid, arylcarboxylic ester, amidyl, ester,alkylcarbonyl, arylcarbonyl, alkylsulfinyl, carboxamido,alkylcarboxamido, arylcarboxamido, sulfonic acid, sulfonic ester,sulfonamido and nitro. Exemplary heterocyclic groups include pyrrolyl,furyl, thienyl, 3-pyrrolinyl,4,5,6-trihydro-2H-pyranyl, pyridinyl,1,4-dihydropyridinyl, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl,oxazolyl, thiazolyl, imidazolyl, indolyl, thiophenyl, furanyl,tetrhydrofuranyl, tetrazolyl, pyrrolinyl, pyrrolindinyl, oxazolindinyl1,3-dioxolanyl, imidazolinyl, imidazolindinyl, pyrazolinyl,pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl,1,2,3-triazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4H-pyranyl,piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl,pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl,benzo(b)thiophenyl, benzimidazolyl, benzothiazolinyl, quinolinyl, andthe like.

“Heterocyclic compounds” refer to mono- and polycyclic compoundscomprising at least one aryl or heterocyclic ring.

“Aryl” refers to a monocyclic, bicyclic, carbocyclic or heterocyclicring system comprising one or two aromatic rings. Exemplary aryl groupsinclude phenyl, pyridyl, napthyl, quinoyl, tetrahydronaphthyl, furanyl,indanyl, indenyl, indoyl, and the like. Aryl groups (including bicyclicaryl groups) can be unsubstituted or substituted with one, two or threesubstituents independently selected from alkyl, alkoxy, alkylthio,amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino,halo, cyano, alkylsulfinyl, hydroxy, carboxyl, carboxylic ester,alkylcarboxylic acid, alkylcarboxylic ester, aryl, arylcarboxylic acid,arylcarboxylic ester, alkylcarbonyl, arylcarbonyl, amidyl, ester,carboxamido, alkylcarboxamido, carbonyl, sulfonic acid, sulfonic ester,sulfonamido and nitro. Exemplary substituted aryl groups includetetrafluorophenyl, pentafluorophenyl, sulfonamide, alkylsulfonyl,arylsulfonyl, and the like.

“Cycloalkenyl” refers to an unsaturated cyclic C₂-C₁₀ hydrocarbon(preferably a C₂-C₈ hydrocarbon, more preferably a C₂-C₆ hydrocarbon)which can comprise one or more carbon-carbon double bonds.

“Alkylaryl” refers to an alkyl group, as defined herein, to which isappended an aryl group, as defined herein. Exemplary alkylaryl groupsinclude benzyl, phenylethyl, hydroxybenzyl, fluorobenzyl,fluorophenylethyl, and the like.

“Arylalkyl” refers to an aryl radical, as defined herein, attached to analkyl radical, as defined herein. Exemplary arylalkyl groups includebenzyl, phenylethyl, 4-hydroxybenzyl, 3-fluorobenzyl,2-fluorophenylethyl, and the like.

“Arylalkenyl” refers to an aryl radical, as defined herein, attached toan alkenyl radical, as defined herein. Exemplary arylalkenyl groupsinclude styryl, propenylphenyl, and the like.

“Cycloalkylalkyl” refers to a cycloalkyl radical, as defined herein,attached to an alkyl radical, as defined herein.

“Cycloalkylalkoxy” refers to a cycloalkyl radical, as defined herein,attached to an alkoxy radical, as defined herein.

“Cycloalkylalkylthio” refers to a cycloalkyl radical, as defined herein,attached to an alkylthio radical, as defined herein.

“Heterocyclicalkyl” refers to a heterocyclic ring radical, as definedherein, attached to an alkyl radical, as defined herein.

“Arylheterocyclic ring” refers to a bi- or tricyclic ring comprised ofan aryl ring, as defined herein, appended via two adjacent carbon atomsof the aryl ring to a heterocyclic ring, as defined herein. Exemplaryarylheterocyclic rings include dihydroindole,1,2,3,4-tetra-hydroquinoline, and the like.

“Alkylheterocyclic ring” refers to a heterocyclic ring radical, asdefined herein, attached to an alkyl radical, as defined herein.Exemplary alkylheterocyclic rings include 2-pyridylmethyl,1-methylpiperidin-2-one-3-methyl, and the like.

“Alkoxy” refers to R₅₀O—, wherein R₅₀ is an alkyl group, as definedherein (preferably a lower alkyl group or a haloalkyl group, as definedherein). Exemplary alkoxy groups include methoxy, ethoxy, t-butoxy,cyclopentyloxy, trifluoromethoxy, and the like.

“Aryloxy” refers to R₅₅O—, wherein R₅₅ is an aryl group, as definedherein. Exemplary arylkoxy groups include napthyloxy, quinolyloxy,isoquinolizinyloxy, and the like.

“Alkylthio” refers to R₅₀S—, wherein R₅₀ is an alkyl group, as definedherein.

“Lower alkylthio” refers to a lower alkyl group, as defined herein,appended to a thio group, as defined herein.

“Arylalkoxy” or “alkoxyaryl” refers to an alkoxy group, as definedherein, to which is appended an aryl group, as defined herein. Exemplaryarylalkoxy groups include benzyloxy, phenylethoxy, chlorophenylethoxy,and the like.

“Alkoxyalkyl” refers to an alkoxy group, as defined herein, appended toan alkyl group, as defined herein. Exemplary alkoxyalkyl groups includemethoxymethyl, methoxyethyl, isopropoxymethyl, and the like.

“Alkoxyhaloalkyl” refers to an alkoxy group, as defined herein, appendedto a haloalkyl group, as defined herein. Exemplary alkoxyhaloalkylgroups include 4-methoxy-2-chlorobutyl and the like.

“Cycloalkoxy” refers to R₅₄O—, wherein R₅₄ is a cycloalkyl group or abridged cycloalkyl group, as defined herein. Exemplary cycloalkoxygroups include cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, and thelike.

“Cycloalkylthio” refers to R₅₄S—, wherein R₅₄ is a cycloalkyl group or abridged cycloalkyl group, as defined herein. Exemplary cycloalkylthiogroups include cyclopropylthio, cyclopentylthio, cyclohexylthio, and thelike.

“Haloalkoxy” refers to an alkoxy group, as defined herein, in which oneor more of the hydrogen atoms on the alkoxy group are substituted withhalogens, as defined herein. Exemplary haloalkoxy groups include1,1,1-trichloroethoxy, 2-bromobutoxy, and the like.

“Hydroxy” refers to —OH.

“Oxo” refers to ═O.

“Oxy” refers to —O⁻R₇₇ ⁺ wherein R₇₇ is an organic or inorganic cation.

“Oxime” refers to ═N—OR₈₁ wherein R₈₁ is a hydrogen, an alkyl group, anaryl group, an alkylsulfonyl group, an arylsulfonyl group, a carboxylicester, an alkylcarbonyl group, an arylcarbonyl group, a carboxamidogroup, an alkoxyalkyl group or an alkoxyaryl group.

“Hydrazone refers to ═N—N(R₈₁)(R′₈₁) wherein R′₈₁ is independentlyselected from R₈₁, and R₈₁ is as defined herein.

“Organic cation” refers to a positively charged organic ion. Exemplaryorganic cations include alkyl substituted ammonium cations, and thelike.

“Inorganic cation” refers to a positively charged metal ion. Exemplaryinorganic cations include Group I metal cations such as for example,sodium, potassium, and the like.

“Hydroxyalkyl” refers to a hydroxy group, as defined herein, appended toan alkyl group, as defined herein.

“Nitrate” refers to —O—NO₂.

“Nitrite” refers to —O—NO.

“Thionitrate” refers to —S—NO₂.

“Thionitrite” and “nitrosothiol” refer to —S—NO.

“Nitro” refers to the group —NO₂ and “nitrosated” refers to compoundsthat have been substituted therewith.

“Nitroso” refers to the group —NO and “nitrosylated” refers to compoundsthat have been substituted therewith.

“Nitrile” and “cyano” refer to —CN.

“Halogen” or “halo” refers to iodine (I), bromine (Br), chlorine (Cl),and/or fluorine (F).

“Amino” refers to —NH₂, an alkylamino group, a dialkylamino group, anarylamino group, a diarylamino group, an alkylarylamino group or aheterocyclic ring, as defined herein.

“Alkylamino” refers to R₅₀NH—, wherein R₅₀ is an alkyl group, as definedherein. Exemplary alkylamino groups include methylamino, ethylamino,butylamino, cyclohexylamino, and the like.

“Arylamino” refers to R₅₅NH—, wherein R₅₅ is an aryl group, as definedherein.

“Dialkylamino” refers to R₅₂R₅₃N—, wherein R₅₂ and R₅₃ are eachindependently an alkyl group, as defined herein. Exemplary dialkylaminogroups include dimethylamino, diethylamino, methyl propargylamino, andthe like.

“Diarylamino” refers to R₅₅R₆₀N—, wherein R₅₅ and R₆₀ are eachindependently an aryl group, as defined herein.

“Alkylarylamino or arylalkylamino” refers to R₅₂R₅₅N—, wherein R₅₂ is analkyl group, as defined herein, and R₅₅ is an aryl group, as definedherein.

“Alkylarylalkylamino” refers to R₅₂R₇₉N—, wherein R₅₂ is an alkyl group,as defined herein, and R₇₉ is an arylalkyl group, as defined herein.

“Alkylcycloalkylamino” refers to R₅₂R₈₀N—, wherein R₅₂ is an alkylgroup, as defined herein, and R₈₀ is an cycloalkyl group, as definedherein.

“Aminoalkyl” refers to an amino group, an alkylamino group, adialkylamino group, an arylamino group, a diarylamino group, analkylarylamino group or a heterocyclic ring, as defined herein, to whichis appended an alkyl group, as defined herein. Exemplary aminoalkylgroups include dimethylaminopropyl, diphenylaminocyclopentyl,methylaminomethyl, and the like.

“Aminoaryl” refers to an aryl group to which is appended an alkylaminogroup, a arylamino group or an arylalkylamino group. Exemplary aminoarylgroups include anilino, N-methylanilino, N-benzylanilino, and the like.

“Thio” refers to —S—.

“Sulfinyl” refers to —S(O)—.

“Methanthial” refers to —C(S)—.

“Thial” refers to ═S.

“Sulfonyl” refers to —S(O)₂—.

“Sulfonic acid” refers to —S(O)₂OR₇₆, wherein R₇₆ is a hydrogen, anorganic cation or an inorganic cation, as defined herein.

“Alkylsulfonic acid” refers to a sulfonic acid group, as defined herein,appended to an alkyl group, as defined herein.

“Arylsulfonic acid” refers to a sulfonic acid group, as defined herein,appended to an aryl group, as defined herein

“Sulfonic ester” refers to —S(O)₂OR₅₈, wherein R₅₈ is an alkyl group, anaryl group, or an aryl heterocyclic ring, as defined herein.

“Sulfonamido” refers to —S(O)₂—N(R₅₁)(R₅₇), wherein R₅₁ and R₅₇ are eachindependently a hydrogen atom, an alkyl group, an aryl group or anarylheterocyclic ring, as defined herein, or R₅₁ and R₅₇ when takentogether are a heterocyclic ring, a cycloalkyl group or a bridgedcycloalkyl group, as defined herein.

“Alkylsulfonamido” refers to a sulfonamido group, as defined herein,appended to an alkyl group, as defined herein.

“Arylsulfonamido” refers to a sulfonamido group, as defined herein,appended to an aryl group, as defined herein.

“Alkylthio” refers to R₅₀S—, wherein R₅₀ is an alkyl group, as definedherein (preferably a lower alkyl group, as defined herein).

“Arylthio” refers to R₅₅S—, wherein R₅₅ is an aryl group, as definedherein.

“Arylalkylthio” refers to an aryl group, as defined herein, appended toan alkylthio group, as defined herein.

“Alkylsulfinyl” refers to R₅₀—S(O)—, wherein R₅₀ is an alkyl group, asdefined herein.

“Alkylsulfonyl” refers to R₅₀—S(O)₂—, wherein R₅₀ is an alkyl group, asdefined herein.

“Alkylsulfonyloxy” refers to R₅₀—S(O)₂—O—, wherein R₅₀ is an alkylgroup, as defined herein.

“Arylsulfinyl” refers to R₅₅—S(O)—, wherein R₅₅ is an aryl group, asdefined herein.

“Arylsulfonyl” refers to R₅₅—S(O)₂—, wherein R₅₅ is an aryl group, asdefined herein.

“Arylsulfonyloxy” refers to R₅₅—S(O)₂—O—, wherein R₅₅ is an aryl group,as defined herein.

“Amidyl” refers to R₅₁C(O)N(R₅₇)— wherein R₅₁ and R₅₇ are eachindependently a hydrogen atom, an alkyl group, an aryl group or anarylheterocyclic ring, as defined herein.

“Ester” refers to R₅₁C(O)O— wherein R₅₁ is a hydrogen atom, an alkylgroup, an aryl group or an arylheterocyclic ring, as defined herein.

“Carbamoyl” refers to —O—C(O)N(R₅₁)(R₅₇), wherein R₅₁ and R₅₇ are eachindependently a hydrogen atom, an alkyl group, an aryl group or anarylheterocyclic ring, as defined herein, or R₅₁ and R₅₇ taken togetherare a heterocyclic ring, a cycloalkyl group or a bridged cycloalkylgroup, as defined herein.

“Carboxyl” refers to —C(O)OR₇₆, wherein R₇₆ is a hydrogen, an organiccation or an inorganic cation, as defined herein.

“Carbonyl” refers to —C(O)—.

“Alkylcarbonyl” refers to R₅₂—C(O)—, wherein R₅₂ is an alkyl group, asdefined herein.

“Arylcarbonyl” refers to R₅₅—C(O)—, wherein R₅₅ is an aryl group, asdefined herein.

“Arylalkylcarbonyl” refers to R₅₅—R₅₂—C(O)—, wherein R₅₅ is an arylgroup, as defined herein, and R₅₂ is an alkyl group, as defined herein.

“Alkylarylcarbonyl” refers to R₅₂—R₅₅—C(O)—, wherein R₅₅ is an arylgroup, as defined herein, and R₅₂ is an alkyl group, as defined herein.

“Heterocyclicalkylcarbonyl” refer to R₇₈C(O)— wherein R₇₈ is aheterocyclicalkyl group, as defined herein.

“Carboxylic ester” refers to —C(O)OR₅₈, wherein R₅₈ is an alkyl group,an aryl group or an aryl heterocyclic ring, as defined herein.

“Alkylcarboxylic acid” and “alkylcarboxyl” refer to an alkyl group, asdefined herein, appended to a carboxyl group, as defined herein.

“Alkylcarboxylic ester” refers to an alkyl group, as defined herein,appended to a carboxylic ester group, as defined herein.

“Arylcarboxylic acid” refers to an aryl group, as defined herein,appended to a carboxyl group, as defined herein.

“Arylcarboxylic ester” and “arylcarboxyl” refer to an aryl group, asdefined herein, appended to a carboxylic ester group, as defined herein.

“Carboxamido” refers to —C(O)N(R₅₁)(R₅₇), wherein R₅₁ and R₅₇ are eachindependently a hydrogen atom, an alkyl group, an aryl group or anarylheterocyclic ring, as defined herein, or R₅₁ and R₅₇ when takentogether are a heterocyclic ring, a cycloalkyl group or a bridgedcycloalkyl group, as defined herein.

“Alkylcarboxamido” refers to an alkyl group, as defined herein, appendedto a carboxamido group, as defined herein.

“Arylcarboxamido” refers to an aryl group, as defined herein, appendedto a carboxamido group, as defined herein.

“Urea” refers to —N(R₅₉)—C(O)N(R₅₁)(R₅₇) wherein R₅₁, R₅₇, and R₅₉ areeach independently a hydrogen atom, an alkyl group, an aryl group or anarylheterocyclic ring, as defined herein, or R₅₁ and R₅₇ taken togetherare a heterocyclic ring, a cycloalkyl group or a bridged cycloalkylgroup, as defined herein.

“Phosphoryl” refers to —P(R₇₀)(R₇₁)(R₇₂), wherein R₇₀ is a lone pair ofelectrons, thial or oxo, and R₇₁ and R₇₂ are each independently acovalent bond, a hydrogen, a lower alkyl, an alkoxy, an alkylamino, ahydroxy, an oxy or an aryl, as defined herein.

Compounds that donate, transfer or release nitric oxide species in vivohave been recognized as having a wide spectrum of advantages andapplications. The invention is based on the unexpected discovery of theeffects of such compounds alone and together with one or more COX-2inhibitors. Treatment or prevention of inflammation, pain and fever;treatment of gastrointestinal disorders and/or improvement of thegastrointestinal properties of COX-2 inhibitors; facilitation of woundhealing; and treatment and/or prevention of renal and/or respiratorytoxicity and cyclooxygenase-2 mediated disorders can be obtained by theuse of COX-2 inhibitors of the invention; or by the use of COX-2inhibitors in conjunction with one or more compounds that donate,release or transfer nitric oxide and/or stimulate endogenous productionof NO and/or EDRF in vivo and/or is a substrate for nitric oxidesynthase, and, optionally, with one or more therapeutic agents.

The COX-2 selective inhibitors, that are optionally nitrosated and/ornitrosylated, can be used alone or in conjunction with one or morecompounds that donate, release or transfer nitric oxide and/or stimulateendogenous production of NO and/or EDRF in vivo and/or is a substratefor nitric oxide synthase, and/or with one or more therapeutic agents,such as for example, steroids, nonsteroidal antiinflammatory compounds(NSAID), 5-lipoxygenase (5-LO) inhibitors, leukotriene B₄ (LTB₄)receptor antagonists, leukotriene A₄ (LTA₄) hydrolase inhibitors,3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors, H₂antagonists, antineoplastic agents, antiplatelet agents, thrombininhibitors, thromboxane inhibitors, decongestants, diuretics, sedatingor non-sedating anti-histamines, inducible nitric oxide synthaseinhibitors, opioids, analgesics, analgesics, Helicobacter pyloriinhibitors, proton pump inhibitors, isoprostane inhibitors, and mixturesof two or more thereof. These novel compounds and novel compositions ofthe present invention are described in more detail herein.

In one embodiment, the invention describes COX-2 inhibitors of Formula(I), and pharmaceutically acceptable salts thereof:

wherein:

R₁ is —S(O)₂—CH₃ or —S(O)₂—NH₂;

R₁′ at each occurrence is independently a hydrogen, a halogen, a methylor CH₂OH;

R₂ is a substituted lower alkyl group, a cycloalkyl group, an aryl groupor a heterocyclic ring;

R₃ is:

-   -   (a) —(C(R₄)(R′₄))_(k)—Y—(C(R₄)(R′₄))_(n)—O—V;    -   (b) —C(Z)-(C(R₄)(R′₄))_(k)—O—V;    -   (c) —C(Z)-(C(R₄)(R′₄))_(k)—Y—(C(R₄)(R′₄))_(n)—O—V;    -   (d)        —(C(R₄)(R′₄))_(k)—Y—(C(R₄)(R′₄))_(n)—C(Z)-(C(R₄)(R′₄))_(n)—O—V;    -   (e) —(C(R₄)(R′₄))_(k)—CH═CH—(C(R₄)(R′₄))_(p)—O—V;    -   (f) —(C(R₄)(R′₄))_(n)—O—V;    -   (g) —(C(R₄)(R′₄))_(n)—W-Q-(C(R₄)(R′₄))_(k)—O—V;    -   (h) —C(Z)-W-Q-(C(R₄)(R′₄))_(k)—O—V;    -   (i) —C(O)—N(R_(i))—O—(C(R₄)(R′₄)_(n)—O—V;    -   (j) —(C(R₄)(R′₄))_(k)—C∂C—(C(R₄)(R′₄))_(p)—O—V;    -   (k) —(C(R₄)(R′₄))_(k)—Y—(C(R₄)(R′₄))_(k)—Y—(C(R₄)(R′₄))_(k)—O—V;    -   (l) —(C(R₄)(R′₄))_(p)-E-N(R_(i))—O—W-Q-(C(R₄)(R′₄)_(k)—O—V;    -   (m) —(C(R₄)(R′₄))_(p)-E-N(R_(i))—O—(C(R₄)(R′₄)_(k)—O—V;    -   (n) —(C(R₄)(R′₄))_(p)—N(R_(i))—O—(C(R₄)(R′₄)_(k)—O—V;    -   (o) —(C(R₄)(R′₄))_(p)—O—N(R_(i))—(C(R₄)(R′₄)_(k)—O—V;    -   (p) —(C(R₄)(R′₄))_(p)—O—N(R_(i))-E-(C(R₄)(R′₄)_(k)—O—V;    -   (q) —(C(R₄)(R′₄))_(p)—O—N(R_(i))-E-W-Q-(C(R₄)(R′₄)_(k)—O—V;    -   (r) —(C(R₄)(R′₄))_(p)—C(Z)-Y—(C(R₄)(R′₄)_(k)—O—V;    -   (s) —(C(R₄)(R′₄))_(p) Y—C(Z)-(C(R₄)(R′₄)_(k)—O—V; or    -   (t) —(C(R₄)(R′₄))_(p)—Y—C(Z)-Y—(C(R₄)(R′₄)_(k)—O—V;

R₄ and R′₄ at each occurrence are independently a hydrogen, a halogen, alower alkyl group, an alkoxy group; or R₄ and R′₄ taken together withthe carbon atom to which they are attached are a cycloalkyl group, anaryl group or a heterocyclic ring;

V is —NO, —NO₂, or a hydrogen;

Y at each occurrence is independently an oxygen, —S(O)_(o)— or—N(R_(a))R_(i)—;

Z is an oxo, a thial, an oxime or a hydrazone;

Q is Y or a covalent bond;

W at each occurrence is independently an aryl group, an alkylaryl group,a heterocyclic ring or an alkylheterocyclic ring;

E is —C(O) or —S(O)_(o);

R_(a) is a lone pair of electron a hydrogen or a lower alkyl group;

R_(i) is a hydrogen, an alkyl, an aryl, an alkylcarboxylic acid, anarylcarboxylic acid, an alkylcarboxylic ester, an arylcarboxylic ester,an alkylcarboxamido, an arylcarboxamido, an alkylaryl, an alkylsulfinyl,an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfinyl, an arylsulfonyl,arylsulphonyloxy, a sulfonamido, a carboxamido, a carboxylic ester, anaminoalkyl, an aminoaryl, —(C(R₄)(R′₄))_(n)—O—V, a bond to an adjacentatom creating a double bond to that atom, —(N₂O₂—)⁻.M⁺, wherein M⁺ is anorganic or inorganic cation;

o is an integer from 0 to 2;

k is an integer from 1 to 6;

p at each occurrence is independently an integer from 0 to 10;

n at each occurrence is independently an integer from 2 to 10; and

with the proviso that when R₂ is cycloalkyl, aryl or a heterocyclicring, R₃ cannot be —(C(R₄)(R′₄))_(n)—O—V, where R₄ and R′₄ at eachoccurrence are independently a hydrogen, a halogen, a lower alkyl group,an alkoxy group and V is hydrogen, as disclosed in, for example, WO98/47509 and WO 99/22720.

In cases where multiple designations of variables that reside insequence are chosen as a “covalent bond” or the integer chosen is 0, theintent is to denote a single covalent bond connecting one radical toanother. For example, E₀ would denote a covalent bond, while E₂ denotes(E-E) and (C(R₄)(R′₄))₂ denotes —C(R₄)(R′₄)—C(R₄)(R′₄)—.

Another embodiment of the invention describes COX-2 inhibitors ofFormula (II), and pharmaceutically acceptable salts thereof:

wherein R₁, R₁′, R₂ and R₃ are as defined herein and

with the proviso that when R₂ is cycloalkyl, aryl or a heterocyclicring, R₃ cannot be —(C(R₄)(R′₄))_(n)—O—V, where R₄ and R′₄ at eachoccurrence are independently a hydrogen, a halogen, a lower alkyl group,an alkoxy group and V is hydrogen, as disclosed in, for example, U.S.Pat. Nos. 5,516,907, 5,753,688, 5,760,068 and in WO 95/15316.

Another embodiment of the invention describes COX-2 inhibitors ofFormula (III), and pharmaceutically acceptable salts thereof:

wherein:

R₅ is:

-   -   (a) —(C(R₄)(R′₄))_(k)—Y—(C(R₄)(R′₄))_(k)—B—(C(R₄)(R′₄))_(k)—O—V;    -   (b) —(C(R₄)(R′₄))_(k)—Y—(C(R₄)(R₄))_(k)-D-(C(R₄)(R′₄))_(k)—O—V;    -   (c) —C(Z)-(C(R₄)(R′₄))_(k)—Y—(C(R₄)(R′₄))_(k)—O—V;    -   (d) —(C(R₄)(R′₄))_(k)—Y—W-Q-C(R₄)(R′₄))_(k)—O—V;    -   (e) —C(Z)-W-Q-(C(R₄)(R′₄))_(k)—O—V;    -   (f) —(C(R₄)(R′₄))_(p)-E-N(R_(i))—O—W-Q-(C(R₄)(R′₄)_(k)—O—V;    -   (g) —(C(R₄)(R′₄))_(p)-E-N(R_(i))—O—(C(R₄)(R′₄)_(k)—O—V;    -   (h) —(C(R₄)(R′₄))_(p)—N(R_(i))—O—(C(R₄)(R′₄)_(k)—O—V;    -   (i) —(C(R₄)(R′₄))_(p)—O—N(R_(i))—(C(R₄)(R′₄)_(k)—O—V;    -   (j) —(C(R₄)(R′₄))_(p)—O—N(R_(i))-E-(C(R₄)(R′₄)_(k)—O—V; or    -   (k)-(C(R₄)(R′₄))_(p)—O—N(R_(i))-E-W-Q-(C(R₄)(R′₄)_(k)—O—V;

B is —C(Z)-, —Y— or a covalent bond;

D is —S(O)_(o) or —N(R_(a))(R_(i)); and

R₁, R₁′, R₂, R₄, R′₄, R_(a), R_(i), E, Y, V, Z, W, Q, o and k are asdefined herein.

In preferred embodiments for the compounds of Formula (I), (II) and(III), R₂ is a cyclopentyl group, a cyclohexyl group, a cycloheptylgroup or a cyclooctyl group optionally substituted with one, two orthree substituents independently selected from a lower alkyl group, analkoxy group, an amino group, a hydroxy group, a nitro group or a halogroup; a phenyl or a pyridyl optionally substituted with one, two orthree substituents independently selected from a lower alkyl group, analkoxy group, an amino group, a hydroxy group, a nitro group or a halogroup.

In more preferred embodiments the compounds of Formulas (I) are:

-   1-(1-cyclohexyl-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-4-hydroxybutan-1-one;-   1-(3-((1Z)-4-(hydroxy)but-1-enyl)-1-cyclohexylpyrazol-5-yl-4-methylsulfonyl)benzene;    4-(3-((3-hydroxypropoxy)methyl)-1-phenylpyrazol-5-yl)-1-(methylsulfonyl)benzene;    1-(3-(difluoro(3-hydroxypropoxy)methyl)-1-phenylpyrazol-5-yl)-4-(methylsulfonyl)benzene;-   1-(1-(4-chlorophenyl)-3-((3-hydroxypropoxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene;-   1-(3-((3-hydroxypropoxy)methyl)-1-(4-methylphenyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene;-   1-(3-((3-hydroxypropoxy)methyl)-1-(4-(trifluoromethyl)phenyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene;-   1-(3-((3-hydroxypropoxy)methyl)-1-(4-methoxyphenyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene;-   1-(3-((1Z)-4-(hydroxy)but-1-enyl)-1-phenylpyrazol-5-yl)-4-methylsulfonyl)benzene;-   4-hydroxy-1-(1-(4-methylphenyl)-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)butan-1-one;-   1-(1-(4-fluorophenyl)-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-4-hydroxybutan-1-one;    1-(1-(4-bromophenyl)-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-4-hydroxybutan-1-one;-   1-(1-cyclohexyl-3-((2-hydroxyethoxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene;-   1-(1-cyclohexyl-3-((3-hydroxypropoxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene;-   1-(1-cyclohexyl-3-((3-(hydroxymethyl)phenoxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene;-   1-(1-(4-fluorophenyl)-3-((3-hydroxypropoxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene;-   1-(3-((3-hydroxybutoxy)methyl)-1-phenylpyrazol-5-yl)-4-(methylsulfonyl)benzene;-   1-(3-((1E)-4-(hydroxy)but-1-enyl)-1-cyclohexylpyrazol-5-yl)-4-methylsulfonyl)benzene;-   1-(1-cyclohexyl-5-(4-(methylsulfonyl)phenyl)-pyrazol-3-yl)-6-hydroxyhexan-1-one;-   4-hydroxy-1-(5-(4-(methylsulfonyl)phenyl)-1-(4-(trifluoromethyl)-phenyl)pyrazol-3-yl)butan-1-one;-   4-hydroxy-1-(1-(4-methoxyphenyl)-5-(4-(methylsulfonyl)phenyl)-pyrazol-3-yl)butan-1-one;-   4-(3-((1E)-3-hydroxyprop-1-enyl)-1-cyclohexylpyrazol-5-yl)-1    (methylsulfonyl)benzene;-   1-(1-cyclohexyl-3-(((2-hydroxyethyl)amino)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene;-   4-(3-(4-hydroxybutanoyl)-5-(4-(methylsulfonyl)phenyl)pyrazolyl)benzenecarbonitrile;-   4-(1-cyclohexyl-3-(4-hydroxybutanoyl)pyrazol-5-yl)benzenesulfonamide;-   1-(1-(4-chlorophenyl)-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-4-hydroxybutan-1-one;-   (1-cyclohexyl-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-N-(2-hydroxyethyl)carboxamide;-   (1-cyclohexyl-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-N-(3-hydroxypropyl)carboxamide;    the nitrosated compounds of Formula (I) are:-   1-(1-cyclooctyl-3-((nitrooxy)methyl)pyrazol-5-yl)-4-methylsulfonyl)benzene;-   1-(1-cycloheptyl-3-((nitrooxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene;-   1-(1-cyclohexyl-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-4-(nitrooxy)butan-1-one-   1-(3-((1Z)-4-(nitrooxy)but-1-enyl)-1-cyclohexylpyrazol-5-yl)-4-(methylsulfonyl)benzene;-   4-(3-((3-(nitrooxy)propoxy)methyl)-1-phenylpyrazol-5-yl)-1-(methylsulfonyl)benzene;-   1-(3-(difluoro(3-(nitrooxy)propoxy)methyl)-1-phenylpyrazol-5-yl)-4-(methylsulfonyl)benzene;-   1-(1-(4-chlorophenyl)-3-((3-(nitrooxy)propoxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene;-   1-(1-(4-methylphenyl)-3-((3-(nitrooxy)propoxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene;-   4-(methylsulfonyl)-1-(3-((3-(nitrooxy)propoxy)methyl)-1-(4-(trifluoromethyl)phenyl)pyrazol-5-yl)benzene;-   1-(1-(4-methoxy-3-nitrophenyl)-3-((3-(nitrooxy)propoxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene;-   1-(3-((1Z)-4-(nitrooxy)but-1-enyl)-1-phenylpyrazol-5-yl)-4-(methylsulfonyl)benzene;-   1-(3-((1E)-4-(nitrooxy)but-1-enyl)-1-phenylpyrazol-5-yl)-4-(methylsulfonyl)benzene;-   1-(1-(4-methylphenyl)-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-4-(nitrooxy)butan-1-one;-   1-(1-(4-fluorophenyl)-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-4-(nitrooxy)butan-1-one-   1-(1-(4-bromophenyl)-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-4-(nitrooxy)butan-1-one;-   1-(1-cyclohexyl-3-((2-(nitrooxy)ethoxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene;-   1-(1-cyclohexyl-3-((3-(nitrooxy)propoxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene;-   1-(1-cyclohexyl-3-((3-((nitrooxy)methyl)phenoxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene;-   1-(1-(4-fluorophenyl)-3-((3-(nitrooxy)propoxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene;-   4-(methylsulfonyl)-1-(3-((3-(nitrooxy)butoxy)methyl)-1-phenylpyrazol-5-yl)benzene;-   1-(3-((1E)-4-(nitrooxy)but-1-enyl)-1-cyclohexylpyrazol-5-yl)-4-(methylsulfonyl)benzene;-   1-(1-cyclohexyl-5-(4-(methylsulfonyl)pyrazol-3-yl)-6-(nitrooxy)hexan-1-one;-   1-(5-(4-(methylsulfonyl)phenyl)-1-(4-(trifluoromethyl)phenyl)pyrazol-3-yl)-4-(nitrooxy)butan-1-one;-   1-(1-(4-methoxyphenyl)-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl-4-(nitrooxy)butan-1-one;-   4-(1-cyclohexyl-3-(2-(nitrooxy)ethyl)pyrazol-5-yl)-1-(methylsulfonyl)benzene;-   4-(1-cyclohexyl-3-(3-(nitrooxy)propyl)pyrazol-5-yl)-1-(methylsulfonyl)benzene;-   1-(5-(4-(methylsulfonyl)phenyl)-1-(2-pyridyl)pyrazol-3-yl)-2-(nitrooxy)ethan-1-one;-   4-(1-(4-methoxyphenyl)-3-((3-(nitrooxy)propoxy)methyl)pyrazol-5-yl)-1-(methylsulfonyl)benzene;-   4-(1-(4-methyl-3-nitrophenyl)-3-((3-(nitrooxy)propoxy)methyl)pyrazol-5-yl)-1-(methylsulfonyl)benzene;-   1-(3-((1E)-3-(nitrooxy)prop-1-enyl)-1-cyclohexylpyrazol-5-yl)-4-(methylsulfonyl)benzene;-   4-(5-(4-(methylsulfonyl)phenyl)-3-(4-(nitrooxy)butanoyl)pyrazolyl)benzenecarbonitrile;-   4-(1-cyclohexyl-3-(4-(nitrooxy)butanoyl)pyrazol-5-yl)benzenesulfonamide;-   1-(1-(4-chlorophenyl)-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-4-(nitrooxy)butan-1-one;-   (1-cyclohexyl-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-N-(2-(nitrooxy)ethyl)carboxamide;-   (1-cyclohexyl-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-N-(3    (nitrooxy)propyl)carboxamide;-   3-(nitrooxy)propyl    4-(5-(4-(methylsulfonyl)phenyl)-1-(4-(trifluoromethyl)-phenyl)pyrazol-3-yl)butanoate;    the compounds of Formula (II) are:-   4-(3-((3-hydroxypropoxy)methyl)-5-(4-methylphenyl)pyrazolyl)benzenesulfonamide;-   1-(3-((1Z)-4-hydroxybut-1-enyl)-5-(3-pyridinyl)pyrazolyl)-4-(methylsulfonyl)benzene;-   4-(5-(4-chlorophenyl)-3-((3-hydroxypropoxy)methyl)pyrazolyl)benzenesulfonamide;-   4-(3-((3-hydroxypropoxy)methyl)-5-phenylpyrazolyl)benzenesulfonamide;-   4-(5-(4-chlorophenyl)-3-((3-hydroxypropoxy)methyl)pyrazolyl)-benzenesulfonamide;    the nitrosated compounds of Formula (III) are:-   4-(5-(4-methylphenyl)-3-((3-(nitrooxy)propoxy)methyl)pyrazolyl)benzenesulfonamide;-   1-(3-((1Z)-4-(nitrooxy)but-1-enyl)-5-(3-pyridyl)pyrazolyl)-4-(methylsulfonyl)benzene;-   4-(5-(4-chlorophenyl)-3-((3-(nitrooxy)propoxy)methyl)pyrazolyl)benzenesulfonamide;-   4-(3-((3-(nitrooxy)propoxy)methyl)-5-phenylpyrazolyl)benzenesulfonamide;-   4-(5-(chlorophenyl)-3-((3-(nitrooxy)propoxy)methyl)benzene-sulfonamide    the compounds of Formula (III) are:-   4-(5-(3-hydroxypropoxy)methyl)-3-phenylisoxazol-4-yl)benzenesulfonamide;-   4-(5-(2-hydroxyethoxy)methyl)-3-phenylisoxazol-4-yl)benzenesulfonamide;-   4-(5-((2,2-difluoro-3-hydroxypropoxy)methyl)-3-phenylisoxazol-4-yl)benzenesulfonamide;-   4-(3-phenyl-5-(2,2,3,3-tetrafluoro-4-hydroxy)methyl)isoxazol-4-yl)benzenesulfonamide;-   4-(5-((2,2,3,3,4,4-hexafluoro-5-hydroxypentyloxy)methyl)-3-phenylisoxazol-4-yl)benzenesulfonamide;-   4-(5-((2-((2-hydroxyethyl)sulfonyl)ethoxy)methyl)-3-phenylisoxazol-4-yl)benzenesulfonamide;    the nitrosated compounds of Formula (III) are:-   4-(5-(3-nitrooxy)propoxy)methyl)-3-phenylisoxazol-4-yl)benzene    sulfonamide;-   4-(5-(2-nitrooxy)ethoxy)methyl-3-phenylisoxazol-4-yl)benzenesulfonamide;-   4-(5-((2,2-difluoro-3-(nitrooxy)propoxy)methyl)-3-phenylisoxazol-4-yl)benzenesulfonamide;-   4-(3-phenyl-5-(2,2,3,3-tetrafluoro-4-hydroxy)methyl)isoxazol-4-yl)benzenesulfonamide;    and-   4-(5-((2,2,3,3,4,4-hexafluoro-5-(nitrooxy)pentyloxy)methyl)-3-phenylisoxazol-4-yl)benzenesulfonamide;-   4-(5-((2-(nitrooxy)ethyl)sulfonyl)ethoxy)methyl)-3-phenylisoxazol-4-yl)benzenesulfonamide;    and pharmaceutically acceptable salts thereof.

Another embodiment of the invention describes the metabolites of thecompounds of Formulas (I), (II) and (III) and pharmaceuticallyacceptable salts thereof. These metabolites, include but are not limitedto, the non-nitrosated and/or non-nitrosylated derivatives, degradationproducts, hydrolysis products, and the like, of the compounds ofFormulas (I), (II) and (III) and pharmaceutically acceptable saltsthereof.

Compounds of the invention that have one or more asymmetric carbon atomsmay exist as the optically pure enantiomers, pure diastereomers,mixtures of enantiomers, mixtures of diastereomers, racemic mixtures ofenantiomers, diastereomeric racemates or mixtures of diastereomericracemates. The invention includes within its scope all such isomers andmixtures thereof.

Another embodiment of the invention provides processes for making thenovel compounds of the invention and to the intermediates useful in suchprocesses. The reactions are performed in solvents appropriate to thereagents and materials used are suitable for the transformations beingeffected. It is understood by one skilled in the art of organicsynthesis that the functionality present in the molecule must beconsistent with the chemical transformation proposed. This will, onoccasion, necessitate judgment by the routineer as to the order ofsynthetic steps, protecting groups required, and deprotectionconditions. Substituents on the starting materials may be incompatiblewith some of the reaction conditions required in some of the methodsdescribed, but alternative methods and substituents compatible with thereaction conditions will be readily apparent to one skilled in the art.The use of sulfur and oxygen protecting groups is well known forprotecting thiol and alcohol groups against undesirable reactions duringa synthetic procedure and many such protecting groups are known anddescribed by, for example, Greene and Wuts, Protective Groups in OrganicSynthesis, Third Edition, John Wiley & Sons, New York (1999).

The chemical reactions described herein are generally disclosed in termsof their broadest application to the preparation of the compounds ofthis invention. Occasionally, the reactions may not be applicable asdescribed to each compound included within the disclosed scope. Thecompounds for which this occurs will be readily recognized by oneskilled in the art. In all such cases, either the reactions can besuccessfully performed by conventional modifications known to oneskilled in the art, e.g., by appropriate protection of interferinggroups, by changing to alternative conventional reagents, by routinemodification of reaction conditions, and the like, or other reactionsdisclosed herein or otherwise conventional, will be applicable to thepreparation of the corresponding compounds of this invention. In allpreparative methods, all starting materials are known or readilyprepared from known starting materials.

The compounds of Formulas (I), (II) and (III) can be synthesized by oneskilled in the art following the methods and examples described herein.The synthesis of the non-nitrosated and/or non-nitrosylated COX-2inhibitors are disclosed in, for example, U.S. Pat. Nos. 5,344,991,5,393,790, 5,466,823, 5,474,995, 5,486,534, 5,504,215, 5,508,426,5,510,496, 5,516,907, 5,521,207, 5,536,752, 5,550,142, 5,563,165,5,616,601, 5,620,999, 5,677,318, 5,668,161, 5,691,374, 5,698,584,5,710,140, 5,753,688, 5,859,257, 5,908,858, 5,945,539, 5,994,381,6,080,876, 6,083,969 and 6,071,954 and in WO 91/19708, WO 94/15932, WO94/26731, WO 94/27980, WO 95/00501, WO 95/11883, WO 95/15315, WO95/15316, WO 95/15317, WO 95/15318, WO 95/18799, WO 95/21817, WO95/30652, WO 96/30656, WO 96/03387, WO 96/03392, WO 96/03385, WO96/03387, WO 96/03388, WO 96/09293, WO 96/09304, WO 96/16934, WO96/19462, WO 96/19463, WO 96/19469, WO 96/25405, WO 96/36617, WO96/36623, WO 97/11704, WO 97/13755, WO 97/27181, WO 97/14691, WO97/16435, WO 97/34882, WO 97/36863, WO 97/40012, WO 97/45420, WO98/00416, WO 98/11080, WO 98/22422, WO 98/41516, WO 98/46594, WO98/52937, WO 99/15531, WO 99/23087, WO 99/33796, WO 99/25695, WO99/61016, WO 99/62884 and WO 99/64415 and in EP0 745 596A1, EP0 087629B1, EP0 418 845B1, EP0 554 829A2, EP0 863 134A1, EP 1 006 114 A1; thedisclosures of each of which are incorporated by reference herein intheir entirety. The COX-2 inhibitor compounds can then be nitrosatedand/or nitrosylated through one or more sites such as oxygen, sulfurand/or nitrogen using the methods described in the examples herein andusing conventional methods known to one skilled in the art. For example,known methods for nitrosating and/or nitrosylating compounds aredescribed in U.S. Pat. Nos. 5,380,758 and 5,703,073; WO 94/03421, WO94/04484, WO 94/12463, WO 95/09831, WO 95/30641, WO 97/27749, WO98/19672, WO 00/25776, WO 01/00563 and WO 01/04082, WO 01/10814, WO01/45703 and Oae et al, Org. Prep. Proc. Int., 15(3):165-198 (1983), thedisclosures of each of which are incorporated by reference herein intheir entirety. The methods of nitrosating and/or nitrosylating thecompounds described in the examples herein and in these references canbe applied by one skilled in the art to produce any of the nitrosatedand/or nitrosylated COX-2 inhibitors described herein.

The compounds of the invention include the COX-2 inhibitors, which havebeen nitrosated and/or nitrosylated through one or more sites such asoxygen (hydroxyl condensation), sulfur (sulfhydryl condensation) and/ornitrogen. The nitrosated and/or nitrosylated COX-2 inhibitors of theinvention donate, transfer or release a biologically active form ofnitrogen monoxide (i.e., nitric oxide).

Nitrogen monoxide can exist in three forms: NO— (nitroxyl), NO.(uncharged nitric oxide) and NO⁺ (nitrosonium). NO. is a highly reactiveshort-lived species that is potentially toxic to cells. This is criticalbecause the pharmacological efficacy of NO depends upon the form inwhich it is delivered. In contrast to the nitric oxide radical (NO.),nitrosonium (NO⁺) does not react with O₂ or O₂ ⁻ species, andfunctionalities capable of transferring and/or releasing NO⁺ and NO— arealso resistant to decomposition in the presence of many redox metals.Consequently, administration of charged NO equivalents (positive and/ornegative) is a more effective means of delivering a biologically activeNO to the desired site of action.

Compounds contemplated for use in the invention (e.g., COX-2 selectiveinhibitor, that can be optionally nitrosated and/or nitrosylated), are,optionally, used in combination with nitric oxide and compounds thatrelease nitric oxide or otherwise directly or indirectly deliver ortransfer a biologically active form of nitrogen monoxide to a site ofits intended activity, such as on a cell membrane in vivo.

The term “nitric oxide” encompasses uncharged nitric oxide (NO.) andcharged nitrogen monoxide species, preferably charged nitrogen monoxidespecies, such as nitrosonium ion (NO⁺) and nitroxyl ion (NO—). Thereactive form of nitric oxide can be provided by gaseous nitric oxide.The nitrogen monoxide releasing, delivering or transferring compoundshave the structure F—NO, wherein F is a nitrogen monoxide releasing,delivering or transferring moiety, and include any and all suchcompounds which provide nitrogen monoxide to its intended site of actionin a form active for its intended purpose. The term “NO adducts”encompasses any nitrogen monoxide releasing, delivering or transferringcompounds, including, for example, S-nitrosothiols, nitrites, nitrates,S-nitrothiols, sydnonimines, 2-hydroxy-2-nitrosohydrazines, (NONOates),(E)-alkyl-2-((E)-hydroxyimino)-5-nitro-3-hexeneamide (FK-409),(E)-alkyl-2-((E)-hydroxyimino)-5-nitro-3-hexeneamines,N-((2Z,3E)-4-ethyl-2-(hydroxyimino)-6-methyl-5-nitro-3-heptenyl)-3-pyridinecarboxamide(FR 146801), nitrosoamines, furoxans as well as substrates for theendogenous enzymes which synthesize nitric oxide. NONOates include, butare not limited to,(Z)-1-(N-methyl-N-(6-(N-methyl-ammoniohexyl)amino))diazen-1-ium-1,2-diolate(“MAHMA/NO”),(Z)-1-(N-(3-ammoniopropyl)-N-(n-propyl)amino)diazen-1-ium-1,2-diolate(“PAPA/NO”),(Z)-1-(N-(3-aminopropyl)-N-(4-(3-aminopropylammonio)butyl)-amino)diazen-1-ium-1,2-diolate (spermine NONOate or “SPER/NO”) andsodium(Z)-1-(N,N-diethylamino)diazenium-1,2-diolate (diethylamineNONOate or “DEA/NO”) and derivatives thereof. NONOates are alsodescribed in U.S. Pat. Nos. 6,232,336, 5,910,316 and 5,650,447, thedisclosures of which are incorporated herein by reference in theirentirety. The “NO adducts” can be mono-nitrosylated, poly-nitrosylated,mono-nitrosated and/or poly-nitrosated at a variety of naturallysusceptible or artificially provided binding sites for biologicallyactive forms of nitrogen monoxide.

One group of NO adducts is the S-nitrosothiols, which are compounds thatinclude at least one —S—NO group. These compounds includeS-nitroso-polypeptides (the term “polypeptide” includes proteins andpolyamino acids that do not possess an ascertained biological function,and derivatives thereof); S-nitrosylated amino acids (including naturaland synthetic amino acids and their stereoisomers and racemic mixturesand derivatives thereof); S-nitrosylated sugars; S-nitrosylated,modified and unmodified, oligonucleotides (preferably of at least 5, andmore preferably 5-200 nucleotides); straight or branched, saturated orunsaturated, aliphatic or aromatic, substituted or unsubstitutedS-nitrosylated hydrocarbons; and S-nitroso heterocyclic compounds.S-nitrosothiols and methods for preparing them are described in U.S.Pat. Nos. 5,380,758 and 5,703,073; WO 97/27749; WO 98/19672; and Oae etal, Org. Prep. Proc. Int., 15(3):165-198 (1983), the disclosures of eachof which are incorporated by reference herein in their entirety.

Another embodiment of the invention is S-nitroso amino acids where thenitroso group is linked to a sulfur group of a sulfur-containing aminoacid or derivative thereof. Such compounds include, for example,S-nitroso-N-acetylcysteine, S-nitroso-captopril,S-nitroso-N-acetylpenicillamine, S-nitroso-homocysteine,S-nitroso-cysteine, S-nitroso-glutathione, S-nitroso-cysteinyl-glycine,and the like.

Suitable S-nitrosylated proteins include thiol-containing proteins(where the NO group is attached to one or more sulfur groups on an aminoacid or amino acid derivative thereof) from various functional classesincluding enzymes, such as tissue-type plasminogen activator (TPA) andcathepsin B; transport proteins, such as lipoproteins; heme proteins,such as hemoglobin and serum albumin; and biologically protectiveproteins, such as immunoglobulins, antibodies and cytokines. Suchnitrosylated proteins are described in WO 93/09806, the disclosure ofwhich is incorporated by reference herein in its entirety. Examplesinclude polynitrosylated albumin where one or more thiol or othernucleophilic centers in the protein are modified.

Other examples of suitable S-nitrosothiols include:

(i) HS(C(R_(e))(R_(f)))_(m)SNO;

(ii) ONS(C(R_(e))(R_(f)))_(m)R_(e); or

(iii) H₂N—CH(CO₂H)—(CH₂)_(m)—C(O)NH—CH(CH₂SNO)—C(O)NH—CH₂—CO₂H;

wherein m is an integer from 2 to 20; R_(e) and R_(f) are eachindependently a hydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy,an hydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring. acycloalkylalkyl, a heterocyclicalkyl, an alkoxy, a haloalkoxy, an amino,an alkylamino, a dialkylamino, an arylamino, a diarylamino, analkylarylamino, an alkoxyhaloalkyl, a haloalkoxy, a sulfonic acid, asulfonic ester, an alkylsulfonic acid, an arylsulfonic acid, anarylalkoxy, an alkylthio, an arylthio, a cyano, an aminoalkyl, anaminoaryl, an aryl, an arylalkyl, a carboxamido, a alkylcarboxamido, anarylcarboxamido, an amidyl, a carboxyl, a carbamoyl, an alkylcarboxylicacid, an arylcarboxylic acid, an alkylcarbonyl, an arylcarbonyl, anester, a carboxylic ester, an alkylcarboxylic ester, an arylcarboxylicester, a haloalkoxy, a sulfonamido, an alkylsulfonamido, anarylsulfonamido, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfonyl,an arylsulfonyloxy, a urea, a nitro, -T-Q-, or—(C(R_(g))(R_(h)))_(k)-T-Q or R_(e) and R_(f) taken together are an oxo,a thial, a heterocyclic ring, a cycloalkyl group, an oxime, a hydrazoneor a bridged cycloalkyl group; Q is —NO or —NO₂; and T is independentlya covalent bond, a carbonyl, an oxygen, —S(O)_(o)— or —N(R_(a))R_(i)—,wherein o is an integer from 0 to 2, R_(a) is a lone pair of electrons,a hydrogen or an alkyl group; R_(i) is a hydrogen, an alkyl, an aryl, analkylcarboxylic acid, an arylcarboxylic acid, an alkylcarboxylic ester,an arylcarboxylic ester, an alkylcarboxamido, an arylcarboxamido, analkylsulfinyl, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfinyl,an arylsulfonyloxy, an arylsulfonyl, a sulfonamido, a carboxamido, acarboxylic ester, an aminoalkyl, an aminoaryl,—CH₂—C(T-Q)(R_(g))(R_(h)), or —(N₂O₂—)⁻.M⁺, wherein M⁺ is an organic orinorganic cation; with the proviso that when R_(i) is—CH₂—C(T-Q)(R_(g))(R_(h)) or —(N₂O₂—).M⁺; then “-T-Q” can be a hydrogen,an alkyl group, an alkoxyalkyl group, an aminoalkyl group, a hydroxygroup or an aryl group; and

R_(g) and R_(h) at each occurrence are independently R_(e);

In cases where R_(e) and R_(f) are a heterocyclic ring or taken togetherR_(e) and R_(f) are a heterocyclic ring, then R_(i) can be a substituenton any disubstituted nitrogen contained within the radical wherein R_(i)is as defined herein.

Nitrosothiols can be prepared by various methods of synthesis. Ingeneral, the thiol precursor is prepared first, then converted to theS-nitrosothiol derivative by nitrosation of the thiol group with NaNO₂under acidic conditions (pH is about 2.5) which yields the S-nitrosoderivative. Acids which can be used for this purpose include aqueoussulfuric, acetic and hydrochloric acids. The thiol precursor can also benitrosylated by reaction with an organic nitrite such as tert-butylnitrite, or a nitrosonium salt such as nitrosonium tetrafluororborate inan inert solvent.

Another group of NO adducts for use in the invention, where the NOadduct is a compound that donates, transfers or releases nitric oxide,include compounds comprising at least one ON—O— or ON—N— group. Thecompounds that include at least one ON—O— or ON—N— group are preferablyON—O— or ON—N-polypeptides (the term “polypeptide” includes proteins andpolyamino acids that do not possess an ascertained biological function,and derivatives thereof); ON—O— or ON—N-amino acids (including naturaland synthetic amino acids and their stereoisomers and racemic mixtures);ON—O— or ON—N-sugars; ON—O— or —ON—N— modified or unmodifiedoligonucleotides (comprising at least 5 nucleotides, preferably 5-200nucleotides); ON—O— or ON—N— straight or branched, saturated orunsaturated, aliphatic or aromatic, substituted or unsubstitutedhydrocarbons; and ON—O—, ON—N— or ON—C-heterocyclic compounds.

Another group of NO adducts for use in the invention include nitratesthat donate, transfer or release nitric oxide, such as compoundscomprising at least one O₂N—O—, O₂N—N— or O₂N—S— group. Preferred amongthese compounds are O₂N—O—, O₂N—N— or O₂N—S— polypeptides (the term“polypeptide” includes proteins and also polyamino acids that do notpossess an ascertained biological function, and derivatives thereof);O₂N—O—, O₂N—N— or O₂N—S—amino acids (including natural and syntheticamino acids and their stereoisomers and racemic mixtures); O₂N—O—,O₂N—N— or O₂N—S— sugars; O₂N—O—, O₂N—N— or O₂N—S— modified andunmodified oligonucleotides (comprising at least 5 nucleotides,preferably 5-200 nucleotides); O₂N—O—, O₂N—N— or O₂N—S— straight orbranched, saturated or unsaturated, aliphatic or aromatic, substitutedor unsubstituted hydrocarbons; and O₂N—O—, O₂N—N— or O₂N—S— heterocycliccompounds. Preferred examples of compounds comprising at least oneO₂N—O—, O₂N—N— or O₂N—S— group include isosorbide dinitrate, isosorbidemononitrate, clonitrate, erythrityl tetranitrate, mannitol hexanitrate,nitroglycerin, pentaerythritoltetranitrate, pentrinitrol,propatylnitrate and organic nitrates with a sulfhydryl-containing aminoacid such as, for example SPM 3672, SPM 5185, SPM 5186 and thosedisclosed in U.S. Pat. Nos. 5,284,872, 5,428,061, 5,661,129, 5,807,847and 5,883,122 and in WO 97/46521, WO 00/54756 and in WO 03/013432, thedisclosures of each of which are incorporated by reference herein intheir entirety.

Another group of NO adducts are N-oxo-N-nitrosoamines that donate,transfer or release nitric oxide and are represented by the formula:R^(1″)R^(2″)N—N(O-M⁺)—NO, where R^(1″) and R^(2″) are each independentlya polypeptide, an amino acid, a sugar, a modified or unmodifiedoligonucleotide, a straight or branched, saturated or unsaturated,aliphatic or aromatic, substituted or unsubstituted hydrocarbon, or aheterocyclic group, and where M⁺ is an organic or inorganic cation, suchas, for example, an alkyl substituted ammonium cation or a Group I metalcation.

The invention is also directed to compounds that stimulate endogenous NOor elevate levels of endogenous endothelium-derived relaxing factor(EDRF) in vivo or are substrates for nitric oxide synthase. Suchcompounds include, for example, L-arginine, L-homoarginine, andN-hydroxy-L-arginine, including their nitrosated and nitrosylatedanalogs (e.g., nitrosated L-arginine, nitrosylated L-arginine,nitrosated N-hydroxy-L-arginine, nitrosylated N-hydroxy-L-arginine,nitrosated L-homoarginine and nitrosylated L-homoarginine), precursorsof L-arginine and/or physiologically acceptable salts thereof,including, for example, citrulline, ornithine, glutamine, lysine,polypeptides comprising at least one of these amino acids, inhibitors ofthe enzyme arginase (e.g., N-hydroxy-L-arginine and2(S)-amino-6-boronohexanoic acid), nitric oxide mediators and/orphysiologically acceptable salts thereof, including, for example,pyruvate, pyruvate precursors, α-keto acids having four or more carbonatoms, precursors of α-keto acids having four or more carbon atoms (asdisclosed in WO 03/017996, the disclosure of which is incorporatedherein in its entirety), and the substrates for nitric oxide synthase,cytokines, adenosin, bradykinin, calreticulin, bisacodyl, andphenolphthalein. EDRF is a vascular relaxing factor secreted by theendothelium, and has been identified as nitric oxide (NO) or a closelyrelated derivative thereof (Palmer et al, Nature, 327:524-526 (1987);Ignarro et al, Proc. Natl. Acad. Sci. USA, 84:9265-9269 (1987)).

The invention is also based on the discovery that compounds andcompositions of the invention may be used in conjunction with othertherapeutic agents for co-therapies, partially or completely, in placeof other conventional antiinflammatory compounds, such as, for example,together with steroids, NSAIDs, 5-lipoxygenase (5-LO) inhibitors,leukotriene B₄ (LTB₄) receptor antagonists, leukotriene A₄ (LTA₄)hydrolase inhibitors, 5-HT agonists, HMG-CoA inhibitors, H₂ receptorantagonists, antineoplastic agents, antiplatelet agents, thrombininhibitors, thromboxane inhibitors, decongestants, diuretics, sedatingor non-sedating anti-histamines, inducible nitric oxide synthaseinhibitors, opiods, analgesics, Helicobacter pylori inhibitors, protonpump inhibitors, isoprostane inhibitors, and mixtures of two or morethereof.

Leukotriene A₄ (LTA₄) hydrolase inhibitors refer to compounds thatselectively inhibit leukotriene A₄ hydrolase with an IC₅₀ of less thanabout 10 μM, and preferably with an IC₅₀ of less than about 1 μM.Suitable LTA₄ hydrolase inhibitors include, but are not limited to,RP-64966, (S,S)-3-amino-4-(4-benzyloxyphenyl)-2-hydroxybutyric acidbenzyl ester,N-(2(R)-(cyclohexylmethyl)-3-(hydroxycarbamoyl)propionyl)-L-alanine,7-(4-(4-ureidobenzyl)phenyl) heptanoic acid and 3(3-(1E,3E-tetradecadienyl)-2-oxiranyl)benzoic acid lithium salt, andmixtures of two or more thereof.

Suitable LTB₄ receptor antagonists include, but are not limited to,ebselen, linazolast, ontazolast; WAY 121006; Bay-x-1005; BI-RM-270;CGS-25019C; ETH-615; MAFP; TMK-688; T-0757; LY 213024, LY 210073, LY223982, LY 233469, LY 255283, LY 264086, LY 292728 and LY 293111;ONO-LB457, ONO-4057, and ONO-LB-448, S-2474, calcitrol; PF 10042; Pfizer105696; RP 66153; SC-53228, SC-41930, SC-50605, SC-51146 and SC-53228;SB-201146 and SB-209247; SKF-104493; SM 15178; TMK-688; BPC 15, andmixtures of two or more thereof. The preferred LTB₄ receptor antagonistsare calcitrol, ebselen, Bay-x-1005, CGS-25019C, ETH-615, LY-293111,ONO-4057 and TMK-688, and mixtures of two or more thereof.

Suitable 5-LO inhibitors include, but are not limited to, A-76745, 78773and ABT761; Bay-x-1005; CMI-392; E-3040; EF-40; F-1322; ML-3000;PF-5901; R-840; rilopirox, flobufen, linasolast, lonapolene, masoprocol,ontasolast, tenidap, zileuton, pranlukast, tepoxalin, rilopirox,flezelastine hydrochloride, enazadrem phosphate, and bunaprolast, andmixtures of two or more thereof. Suitable 5-LO inhibitors are alsodescribed more fully in WO 97/29776, the disclosure of which isincorporated herein by reference in its entirety.

Suitable 5-HT agonists, include, but are not limited to, rizatriptan,sumatriptan, naratriptan, zolmitroptan, eleptriptan, almotriptan, ergotalkaloids. ALX 1323, Merck L 741604 SB 220453 and LAS 31416. Suitable5-HT agonists are described more fully in WO 0025779, and in WO00/48583. 5-HT agonists refers to a compound that is an agonist to any5-HT receptor, including but not limited to, 5-HT₁ agonists, 5-HT_(1B)agonists and 5-HT_(1D) agonists, and the like.

Suitable steroids, include, but are not limited to, budesonide,dexamethasone, corticosterone, prednisolone, and the like. Suitablesteroids are described more fully in the literature, such as in theMerck Index on CD-ROM, 13^(th) Edition.

Suitable HMG CoA inhibitors, include, but are not limited to, reductaseand synthase inhibitors, such as, for example, squalene synthetaseinhibitors, benzodiazepine squalene synthase inhibitors, squaleneepoxidase inhibitors, acyl-coenzyme A, bile acid sequestrants,cholesterol absorption inhibitors, and the like. Suitable HMG CoAinhibitors include simvastatin, pravastatin, lovastatin, mevastatin,fluvastatin, atorvastatin, cerivastatin, and the like, and are describedmore fully in U.S. Pat. No. 6,245,797 and WO 99/20110, the disclosuresof which are incorporated herein by reference in their entirety.

Suitable NSAIDs, include, but are not limited to, acetaminophen,aspirin, diclofenac, ibuprofen, ketoprofen, naproxen, indomethacin,including but not limited to prodrugs thereof, and the like. SuitableNSAIDs are described more fully in the literature, such as in Goodmanand Gilman, The Pharmacological Basis of Therapeutics (9th Edition),McGraw-Hill, 1995, Pgs. 617-657; the Merck Index on CD-ROM, 13^(th)Edition; and in U.S. Pat. Nos. 6,057,347 and 6,297,260 assigned toNitroMed. Inc., the disclosures of which are incorporated herein byreference in their entirety.

Suitable H₂ receptor anatgonists, include, but are not limited to,cimetidine, roxatidine, rantidine and the like. Suitable H₂ receptorantagonists are described more fully in the literature, such as inGoodman and Gilman, The Pharmacological Basis of Therapeutics (9thEdition), McGraw-Hill, 1995, Pgs. 901-915; the Merck Index on CD-ROM,13^(th) Edition; and in WO 00/28988 assigned to NitroMed. Inc., thedisclosures of which are incorporated herein by reference in theirentirety.

Suitable antineoplastic agents, include but are not limited to,5-FU-fibrinogen, acanthifolic acid, aminothiadiazole, altretamine,anaxirone, aclarubicin and the like. Suitable antineoplastic agents arealso described in U.S. Pat. No. 6,025,353 and WO 00/38730, thedisclosures of which are incorporated herein by reference in theirentirety.

Suitable antiplatelet agents, include but are not limited to, aspirin,ticlopidine, dipyridamole, clopidogrel, glycoprotein IIb/IIIa receptorantagonists, and the like. Suitable antineoplastic agents are alsodescribed in WO 99/45913, the disclosure of which is incorporated hereinby reference in its entirety. In a preferred embodiment of theinvention, the antiplatelet agent is aspirin, more preferably, low-doseaspirin (i.e. 75 mg-100 mg/day).

Suitable thrombin inhibitors, include but are not limited to,N′-((1-(aminoiminomethyl)-4-piperidinyl)methyl)-N-(3,3-diphenylpropinyl)-L-prolineamide),3-(2-phenylethylamino)-6-methyl-1-(2-amino-6-methyl-5-methylene-carboxamidomethylpyridinyl)-2-pyrazinone,3-(2-phenethylamino)-6-methyl-1-(2-amino-6-methyl-5-methylenecarboxamidomethylpyridinyl)-2-pyridinone,and the like. Suitable thrombin inhibitors are also described in WO00/18352, the disclosure of which is incorporated herein by reference inits entirety.

Suitable thromboxane inhibitors, include but are not limited tothromboxane synthase inhibitors, thromboxane receptor antagonists, andthe like. Suitable thromboxane inhibitors, are also described in WO01/87343, the disclosure of which is incorporated herein by reference inits entirety.

Suitable decongestants include, but are not limited to, phenylephrine,phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine,naphazoline, xylometazoline, propylhexedrine, levo-desoxyephedrine, andthe like.

Suitable antitussives include, but are not limited to, codeine,hydrocodone, caramiphen, carbetapentane, dextramethorphan, and the like.

Suitable proton pump inhibitors, include, but are not limited to,omeprazole, esomeprazole, lansoprazole, rabeprazole, pantoprazole, andthe like. Suitable proton pump inhibitors are described more fully inthe literature, such as in Goodman and Gilman, The Pharmacological Basisof Therapeutics (9th Edition), McGraw-Hill, 1995, Pgs. 901-915; theMerck Index on CD-ROM, 13^(th) Edition; and in WO 00/50037 assigned toNitroMed. Inc., the disclosures of which are incorporated herein byreference in their entirety.

The compounds and compositions of the invention, may also be used incombination therapies with opioids and other analgesics, including, butnot limited to, narcotic analgesics, Mu receptor antagonists, Kappareceptor antagonists, non-narcotic (i.e. non-addictive) analgesics,monoamine uptake inhibitors, adenosine regulating agents, cannabinoidderivatives, neurokinin 1 receptor antagonists, Substance P antagonists,neurokinin-1 receptor antagonists, sodium channel blockers,N-methyl-D-aspartate receptor antagonists, and mixtures of two or morethereof. Preferred combination therapies would be with morphine,meperidine, codeine, pentazocine, buprenorphine, butorphanol, dezocine,meptazinol, hydrocodone, oxycodone, methadone, Tramadol ((+)enantiomer), DuP 747, Dynorphine A, Enadoline, RP-60180, HN-11608,E-2078, ICI-204448, acetominophen (paracetamol), propoxyphene,nalbuphine, E-4018, filenadol, mirtentanil, amitriptyline, DuP631,Tramadol ((−) enantiomer), GP-531, acadesine, AKI-1, AKI-2, GP-1683,GP-3269, 4030W92, tramadol racemate, Dynorphine A, E-2078, AXC3742,SNX-111, ADL2-1294, ICI-204448, CT-3, CP-99,994, CP-99,994, and mixturesof two or more thereof.

The compounds and compositions of the invention can also be used incombination with inducible nitric oxide synthase (iNOS) inhibitors.Suitable iNOS inhibitors are disclosed in U.S. Pat. Nos. 5,132,453 and5,273,875, and in WO 97/38977 and WO 99/18960, the disclosures of eachof which are incorporated by reference herein in their entirety.

The invention is also based on the discovery that the administration ofa therapeutically effective amount of the compounds and compositionsdescribed herein is effective for treating inflammation, pain (bothchronic and acute), and fever, such as, for example, analgesic in thetreatment of pain, including, but not limited to headaches, migraines,postoperative pain, dental pain, muscular pain, and pain resulting fromcancer; as an antipyretic for the treatment of fever, including but notlimited to, rheumatic fever, symptoms associated with influenza or otherviral infections, common cold, low back and neck pain, dysmenorrhea,headache, toothache, sprains, strains, myositis, neuralgia, synovitis;arthritis, including but not limited to rheumatoid arthritis,degenerative joint disease (osteoarthritis), spondyloarthropathies,gouty arthritis, systemic lupus erythematosus and juvenile arthritis.For example, the patient can be administered a therapeutically effectiveamount of at least one COX-2 selective inhibitor, that is optionallynitrosated and/or nitrosylated. In another embodiment, the patient canbe administered a therapeutically effective amount of at least one COX-2selective inhibitor, that is optionally nitrosated and/or nitrosylated,and at least one compound that donates, transfers or releases nitricoxide, or elevates levels of endogenous EDRF or nitric oxide, or is asubstrate for nitric oxide synthase. In yet another embodiment, thepatient can be administered a therapeutically effective amount of atleast one COX-2 selective inhibitor, that is optionally nitrosatedand/or nitrosylated, and, at least one therapeutic agent, including butnot limited to, steroids, nonsteroidal antiinflammatory compounds(NSAID), 5-lipoxygenase (5-LO) inhibitors, leukotriene B₄ (LTB₄)receptor antagonists, leukotriene A₄ (LTA₄) hydrolase inhibitors, 5-HTagonists, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors, H₂antagonists, antineoplastic agents, antiplatelet agents, thrombininhibitors, thromboxane inhibitors, decongestants, diuretics, sedatingor non-sedating anti-histamines, inducible nitric oxide synthaseinhibitors, opioids, analgesics, Helicobacter pylori inhibitors, protonpump inhibitors, isoprostane inhibitors, and, optionally, at least onecompound that donates, transfers or releases nitric oxide, or elevateslevels of endogenous EDRF or nitric oxide, or is a substrate for nitricoxide synthase. The compounds can be administered separately or in theform of a composition.

Another embodiment of the invention provides methods for treatinggastrointestinal disorders and/or improving the gastrointestinalproperties of the COX-2 selective inhibitor by administering to thepatient in need thereof a therapeutically effective amount of thecompounds and/or compositions described herein. Such gastrointestinaldisorders refer to any disease or disorder of the upper gastrointestinaltract (e.g., esophagus, the stomach, the duodenum, jejunum) including,for example, inflammatory bowel disease, Crohn's disease, gastritis,irritable bowel syndrome, ulcerative colitis, peptic ulcers, stressulcers, gastric hyperacidity, dyspepsia, gastroparesis,Zollinger-Ellison syndrome, gastroesophageal reflux disease, bacterialinfections (including, for example, a Helicobacter Pylori associateddisease), short-bowel (anastomosis) syndrome, hypersecretory statesassociated with systemic mastocytosis or basophilic leukemia andhyperhistaminemia, and bleeding peptic ulcers that result, for example,from neurosurgery, head injury, severe body trauma or burns. Forexample, the patient can be administered a therapeutically effectiveamount of at least one COX-2 selective inhibitor, that is optionallynitrosated and/or nitrosylated In another embodiment, the patient can beadministered a therapeutically effective amount of at least one COX-2selective inhibitor, that is optionally nitrosated and/or nitrosylated,and at least one compound that donates, transfers or releases nitricoxide, or elevates levels of endogenous EDRF or nitric oxide, or is asubstrate for nitric oxide synthase. In yet another embodiment, thepatient can be administered a therapeutically effective amount of atleast one COX-2 selective inhibitor, that is optionally nitrosatedand/or nitrosylated, and, at least one therapeutic agent, including butnot limited to, including but not limited to, steroids, nonsteroidalantiinflammatory compounds (NSAID), 5-lipoxygenase (5-LO) inhibitors,leukotriene B₄ (LTB₄) receptor antagonists, leukotriene A₄ (LTA₄)hydrolase inhibitors, 5-HT agonists, 3-hydroxy-3-methylglutaryl coenzymeA (HMG-CoA) inhibitors, H₂ antagonists, antineoplastic agents,antiplatelet agents, thrombin inhibitors, thromboxane inhibitors,decongestants, diuretics, sedating or non-sedating anti-histamines,inducible nitric oxide synthase inhibitors, opioids, analgesics,Helicobacter pylori inhibitors, proton pump inhibitors, isoprostaneinhibitors, and, optionally, at least one compound that donates,transfers or releases nitric oxide, or elevates levels of endogenousEDRF or nitric oxide, or is a substrate for nitric oxide synthase. Thecompounds can be administered separately or in the form of acomposition.

Yet another embodiment of the invention provides methods forfacilitating wound healing (such as, for example, ulcer healing, bonehealing including osteoporosis) by administering to the patient in needthereof a therapeutically effective amount of the compounds and/orcompositions described herein. Wound refers to, and includes, any lesionthat is characterized by loss of tissue, and, includes, but is notlimited to, ulcers, cuts, burns, bone fractures, orthopedic procedure,wound infliction, and the like. Ulcers refers to lesions of the uppergastrointestinal tract lining that are characterized by loss of tissue,and, include, but are not limited to, gastric ulcers, duodenal ulcers,gastritis, and the like. For example, the patient can be administered atherapeutically effective amount of at least one COX-2 selectiveinhibitor, that is optionally nitrosated and/or nitrosylated In anotherembodiment, the patient can be administered a therapeutically effectiveamount of at least one COX-2 selective inhibitor, that is optionallynitrosated and/or nitrosylated, and at least one compound that donates,transfers or releases nitric oxide, or elevates levels of endogenousEDRF or nitric oxide, or is a substrate for nitric oxide synthase. Inyet another embodiment, the patient can be administered atherapeutically effective amount of at least one COX-2 selectiveinhibitor, that is optionally nitrosated and/or nitrosylated, and, atleast one therapeutic agent, and, optionally, at least one nitric oxidedonor. The compounds can be administered separately or in the form of acomposition.

Another embodiment of the invention provides methods to decrease orreverse renal and/or other toxicities (such as, for example, kidneytoxicity, respiratory toxicity) by administering to a patient in needthereof a therapeutically effective amount of the compounds and/orcompositions described herein. For example, the patient can beadministered a therapeutically effective amount of at least one COX-2selective inhibitor, that is optionally nitrosated and/or nitrosylated.In another embodiment, the patient can be administered a therapeuticallyeffective amount of at least one COX-2 selective inhibitor, that isoptionally nitrosated and/or nitrosylated, and at least one nitric oxidedonor. In yet another embodiment, the patient can be administered atherapeutically effective amount of at least one COX-2 selectiveinhibitor, that is optionally nitrosated and/or nitrosylated, and atleast one therapeutic agent, and, optionally, at least one nitric oxidedonor. The compounds can be administered separately or in the form of acomposition.

Another embodiment of the invention provides methods to treat or preventdisorders resulting from elevated levels of COX-2 by administering to apatient in need thereof a therapeutically effective amount of thecompounds and/or compositions described herein. For example, the patientcan be administered a therapeutically effective amount of at least oneCOX-2 selective inhibitor, that is optionally nitrosated and/ornitrosylated. In another embodiment, the patient can be administered atherapeutically effective amount of at least one COX-2 selectiveinhibitor, that is optionally nitrosated and/or nitrosylated, and atleast one compound that donates, transfers or releases nitric oxide, orelevates levels of endogenous EDRF or nitric oxide, or is a substratefor nitric oxide synthase. In yet another embodiment, the patient can beadministered a therapeutically effective amount of at least one COX-2selective inhibitor, that is optionally nitrosated and/or nitrosylated,and at least one therapeutic agent, including but not limited to,steroids, a nonsteroidal antiinflammatory compounds (NSAID),5-lipoxygenase (5-LO) inhibitors, leukotriene B₄ (LTB₄) receptorantagonists, leukotriene A₄ (LTA₄) hydrolase inhibitors, 5-HT agonists,3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors, H₂antagonists, antineoplastic agents, antiplatelet agents, thrombininhibitors, thromboxane inhibitors, decongestants, diuretics, sedatingor non-sedating anti-histamines, inducible nitric oxide synthaseinhibitors, opioids, analgesics, Helicobacter pylori inhibitors, protonpump inhibitors, isoprostane inhibitors, and, optionally, at least onecompound that donates, transfers or releases nitric oxide, or elevateslevels of endogenous EDRF or nitric oxide, or is a substrate for nitricoxide synthase. The compounds can be administered separately or in theform of a composition.

Disorders resulting from elevated levels of COX-2 (e.g., COX-2 mediateddisorders) include, but are not limited to, for example, angiogenesis,arthritis, asthma, bronchitis, menstrual cramps, premature labor,tendinitis, bursitis; skin-related conditions, such as, for example,psoriasis, eczema, surface wounds, burns and dermatitis; post-operativeinflammation including from ophthalmic surgery, such as, for example,cataract surgery and refractive surgery, and the like; treatment ofneoplasia, such as, for example, brain cancer, bone cancer, epithelialcell-derived neoplasia (epithelial carcinoma), such as, for example,basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, such as,for example, lip cancer, mouth cancer, esophageal cancer, small bowelcancer and stomach cancer, colon cancer, liver cancer, bladder cancer,pancreas cancer, ovary cancer, cervical cancer, lung cancer, breastcancer and skin cancer, such as squamous cell and basal cell cancers,prostate cancer, renal cell carcinoma, and other known cancers thateffect epithelial cells throughout the body, benign and canceroustumors, growths, polyps, adenomatous polyps, including, but not limitedto, familial adenomatous polyposis, fibrosis resulting from radiationtherapy, and the like; treatment of inflammatory processes in diseases,such as, for example, vascular diseases, migraine headaches,periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease,scleredoma, rheumatic fever, type I diabetes, neuromuscular junctiondisease including myasthenia gravis, white matter disease includingmultiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome,polymyositis, gingivitis, nephritis, hypersensitivity, swellingoccurring after injury, myocardial ischemia, and the like; treatment ofophthalmic diseases and disorders, such as, for example, retinitis,retinopathies, uveitis, ocular photophobia, acute injury to the eyetissue, glaucoma, inflammation of the eye and elevation of intraocularpressure and the like; treatment of pulmonary inflammation, such as, forexample, those associated with viral infections and cystic fibrosis, andthe like; treatment of central nervous system disorders, such as, forexample, cortical dementia including Alzheimer's disease, vasculardementia, multi-infarct dementia, pre-senile dementia, alcoholicdementia, senile dementia, and central nervous system damage resultingfrom stroke, ischemia and trauma, and the like; treatment of allergicrhinitis, respiratory distress syndrome, endotoxin shock syndrome,atherosclerosis; treatment of inflammations and/or microbial infectionsincluding, for example, inflammations and/or infections of the eyes,ears, nose, throat, and/or skin; treatment and/or prevention ofcardiovascular disorders, such as, for example, coronary artery disease,aneurysm, arteriosclerosis, atherosclerosis, including, but not limitedto, cardiac transplant atherosclerosis, myocardial infarction,hypertension, ischemia, embolism, stroke, thrombosis, venous thrombosis,thromboembolism, thrombotic occlusion and reclusion, restenosis, angina,unstable angina, shock, heart failure, coronary plaque inflammation,bacterial-induced inflammation, such as, for example, Chlamydia-inducedinflammation, viral induced inflammation, inflammation associated withsurgical procedures, such as, for example, vascular grafting, coronaryartery bypass surgery, revascularization procedures, such as, forexample, angioplasty, stent placement, endarterectomy, vascularprocedures involving arteries, veins, capillaries, and the like;treatment and/or prevention of urinary and/or urological disorders, suchas, for example, incontinence and the like; treatment and/or preventionof endothelial dysfunctions, such as, for example, diseases accompanyingthese dysfunctions, endothelial damage from hypercholesterolemia,endothelial damage from hypoxia, endothelial damage from mechanical andchemical noxae, especially during and after drug, and mechanicalreopening of stenosed vessels, for example, following percutaneoustransluminal angiography (PTA) and percutaneous transluminal coronaryangiography (PTCA), endothelial damage in postinfarction phase,endothelium-mediated reocculusion following bypass surgery, blood supplydisturbances in peripheral arteries, as well as, cardiovasculardiseases, and the like; methods for treating and/or preventing tissuedeterioration, such as, for example, for organ transplants, and thelike; disorders treated by the inhibition and/or prevention ofactivation, adhesion and infiltration of neutrophils at the site ofinflammation; and disorders treated by the inhibition and/or preventionof platelet aggregation. The compounds and compositions of the inventioncan also be used as a pre-anesthetic medication in emergency operationsto reduce the danger of aspiration of acidic gastric contents.

Another embodiment of the invention provides methods for improving thecardiovascular profile of COX-2 selective inhibitors by administering toa patient in need thereof a therapeutically effective amount of thecompounds and/or compositions described herein. For example, the patientcan be administered a therapeutically effective amount of at least onenitrosated and/or nitrosylated COX-2 selective inhibitor of theinvention. In another embodiment, the patient can be administered atherapeutically effective amount of at least one COX-2 selectiveinhibitor, that is optionally nitrosated and/or nitrosylated, and atleast one nitric oxide donor. In yet another embodiment, the patient canbe administered a therapeutically effective amount of at least one COX-2selective inhibitor, that is optionally nitrosated and/or nitrosylated,at least one of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)inhibitors, antiplatelet agents, thrombin inhibitors, thromboxaneinhibitors, and, optionally, at least one nitric oxide donor. Thecompounds can be administered separately or in the form of acomposition.

When administered separately, the COX-2 selective inhibitor, that isoptionally nitrosated and/or nitrosylated, can be administered about thesame time as part of the overall treatment regimen i.e., as acombination therapy. “About the same time” includes administering theCOX-2 selective inhibitor, that is optionally nitrosated and/ornitrosylated, simultaneously, sequentially, at the same time, atdifferent times on the same day, or on different days, as long as theyare administered as part of an overall treatment regimen, i.e.,combination therapy or a therapeutic cocktail.

When administered in vivo, the compounds and compositions of theinvention can be administered in combination with pharmaceuticallyacceptable carriers and in dosages described herein. When the compoundsand compositions of the invention are administered as a combination ofat least one COX-2 selective inhibitor and/or at least one nitrosatedand/or nitrosylated COX-2 selective inhibitor and/or at least one nitricoxide donor and/or therapeutic agent, they can also be used incombination with one or more additional compounds which are known to beeffective against the specific disease state targeted for treatment. Thenitric oxide donors, therapeutic agents and/or other additionalcompounds can be administered simultaneously with, subsequently to, orprior to administration of the COX-2 selective inhibitor and/ornitrosated and/or nitrosylated COX-2 selective inhibitor.

The compounds and compositions of the invention can be administered byany available and effective delivery system including, but not limitedto, orally, bucally, parenterally, by inhalation spray, by topicalapplication, by injection, transdermally, or rectally (e.g., by the useof suppositories) in dosage unit formulations containing conventionalnontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles,as desired. Parenteral includes subcutaneous injections, intravenous,intramuscular, intrasternal injection, or infusion techniques.

Transdermal compound administration, which is known to one skilled inthe art, involves the delivery of pharmaceutical compounds viapercutaneous passage of the compound into the systemic circulation ofthe patient. Topical administration can also involve the use oftransdermal administration such as transdermal patches or iontophoresisdevices. Other components can be incorporated into the transdermalpatches as well. For example, compositions and/or transdermal patchescan be formulated with one or more preservatives or bacteriostaticagents including, but not limited to, methyl hydroxybenzoate, propylhydroxybenzoate, chlorocresol, benzalkonium chloride, and the like.Dosage forms for topical administration of the compounds andcompositions can include creams, sprays, lotions, gels, ointments, eyedrops, nose drops, ear drops, and the like. In such dosage forms, thecompositions of the invention can be mixed to form white, smooth,homogeneous, opaque cream or lotion with, for example, benzyl alcohol 1%or 2% (wt/wt) as a preservative, emulsifying wax, glycerin, isopropylpalmitate, lactic acid, purified water and sorbitol solution. Inaddition, the compositions can contain polyethylene glycol 400. They canbe mixed to form ointments with, for example, benzyl alcohol 2% (wt/wt)as preservative, white petrolatum, emulsifying wax, and tenox II(butylated hydroxyanisole, propyl gallate, citric acid, propyleneglycol). Woven pads or rolls of bandaging material, e.g., gauze, can beimpregnated with the compositions in solution, lotion, cream, ointmentor other such form can also be used for topical application. Thecompositions can also be applied topically using a transdermal system,such as one of an acrylic-based polymer adhesive with a resinouscrosslinking agent impregnated with the composition and laminated to animpermeable backing.

Solid dosage forms for oral administration can include capsules,tablets, effervescent tablets, chewable tablets, pills, powders,sachets, granules and gels. In such solid dosage forms, the activecompounds can be admixed with at least one inert diluent such assucrose, lactose or starch. Such dosage forms can also comprise, as innormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, effervescent tablets, and pills, the dosage forms can alsocomprise buffering agents. Soft gelatin capsules can be prepared tocontain a mixture of the active compounds or compositions of theinvention and vegetable oil. Hard gelatin capsules can contain granulesof the active compound in combination with a solid, pulverulent carriersuch as lactose, saccharose, sorbitol, mannitol, potato starch, cornstarch, amylopectin, cellulose derivatives of gelatin. Tablets and pillscan be prepared with enteric coatings.

Liquid dosage forms for oral administration can include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions can also comprise adjuvants, such as wetting agents,emulsifying and suspending agents, and sweetening, flavoring, andperfuming agents.

Suppositories for vaginal or rectal administration of the compounds andcompositions of the invention, such as for treating pediatric fever andthe like, can be prepared by mixing the compounds or compositions with asuitable nonirritating excipient such as cocoa butter and polyethyleneglycols which are solid at room temperature but liquid at rectaltemperature, such that they will melt in the rectum and release thedrug.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions can be formulated according to the known artusing suitable dispersing agents, wetting agents and/or suspendingagents. The sterile injectable preparation can also be a sterileinjectable solution or suspension in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that can be used are water,Ringer's solution, and isotonic sodium chloride solution. Sterile fixedoils are also conventionally used as a solvent or suspending medium.

The compositions of this invention can further include conventionalexcipients, i.e., pharmaceutically acceptable organic or inorganiccarrier substances suitable for parenteral application which do notdeleteriously react with the active compounds. Suitable pharmaceuticallyacceptable carriers include, for example, water, salt solutions,alcohol, vegetable oils, polyethylene glycols, gelatin, lactose,amylose, magnesium stearate, talc, surfactants, silicic acid, viscousparaffin, perfume oil, fatty acid monoglycerides and diglycerides,petroethral fatty acid esters, hydroxymethyl-cellulose,polyvinylpyrrolidone, and the like. The pharmaceutical preparations canbe sterilized and if desired, mixed with auxiliary agents, e.g.,lubricants, preservatives, stabilizers, wetting agents, emulsifiers,salts for influencing osmotic pressure, buffers, colorings, flavoringand/or aromatic substances and the like which do not deleteriously reactwith the active compounds. For parenteral application, particularlysuitable vehicles consist of solutions, preferably oily or aqueoussolutions, as well as suspensions, emulsions, or implants. Aqueoussuspensions may contain substances which increase the viscosity of thesuspension and include, for example, sodium carboxymethyl cellulose,sorbitol and/or dextran. Optionally, the suspension may also containstabilizers.

The composition, if desired, can also contain minor amounts of wettingagents, emulsifying agents and/or pH buffering agents. The compositioncan be a liquid solution, suspension, emulsion, tablet, pill, capsule,sustained release formulation, or powder. The composition can beformulated as a suppository, with traditional binders and carriers suchas triglycerides. Oral formulations can include standard carriers suchas pharmaceutical grades of mannitol, lactose, starch, magnesiumstearate, sodium saccharine, cellulose, magnesium carbonate, and thelike.

Various delivery systems are known and can be used to administer thecompounds or compositions of the invention, including, for example,encapsulation in liposomes, microbubbles, emulsions, microparticles,microcapsules and the like. The required dosage can be administered as asingle unit or in a sustained release form.

The bioavailabilty of the compositions can be enhanced by micronizationof the formulations using conventional techniques such as grinding,milling, spray drying and the like in the presence of suitableexcipients or agents such as phospholipids or surfactants.

The preferred methods of administration of the COX-2 selectiveinhibitors and compositions for the treatment of gastrointestinaldisorders are orally, bucally or by inhalation. The preferred methods ofadministration for the treatment of inflammation and microbialinfections are orally, bucally, topically, transdermally or byinhalation.

The compounds and compositions of the invention can be formulated aspharmaceutically acceptable salt forms. Pharmaceutically acceptablesalts include, for example, alkali metal salts and addition salts offree acids or free bases. The nature of the salt is not critical,provided that it is pharmaceutically-acceptable. Suitablepharmaceutically-acceptable acid addition salts may be prepared from aninorganic acid or from an organic acid. Examples of such inorganic acidsinclude, but are not limited to, hydrochloric, hydrobromic, hydroiodic,nitric, carbonic, sulfuric and phosphoric acid and the like. Appropriateorganic acids include, but are not limited to, aliphatic,cycloaliphatic, aromatic, heterocyclic, carboxylic and sulfonic classesof organic acids, such as, for example, formic, acetic, propionic,succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic,glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic,anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic,mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic,benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic,sulfanilic, stearic, algenic, β-hydroxybutyric, cyclohexylaminosulfonic,galactaric and galacturonic acid and the like. Suitablepharmaceutically-acceptable base addition salts include, but are notlimited to, metallic salts made from aluminum, calcium, lithium,magnesium, potassium, sodium and zinc or organic salts made fromprimary, secondary and tertiary amines, cyclic amines,N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine) and procaine and thelike. All of these salts may be prepared by conventional means from thecorresponding compound by reacting, for example, the appropriate acid orbase with the compound.

While individual needs may vary, determination of optimal ranges foreffective amounts of the compounds and/or compositions is within theskill of the art. Generally, the dosage required to provide an effectiveamount of the compounds and compositions, which can be adjusted by oneof ordinary skill in the art, will vary depending on the age, health,physical condition, sex, diet, weight, extent of the dysfunction of therecipient, frequency of treatment and the nature and scope of thedysfunction or disease, medical condition of the patient, the route ofadministration, pharmacological considerations such as the activity,efficacy, pharmacokinetic and toxicology profiles of the particularcompound used, whether a drug delivery system is used, and whether thecompound is administered as part of a drug combination.

The amount of a given COX-2 selective inhibitor of the invention thatwill be effective in the treatment of a particular disorder or conditionwill depend on the nature of the disorder or condition, and can bedetermined by standard clinical techniques, including reference toGoodman and Gilman, supra; The Physician's Desk Reference, MedicalEconomics Company, Inc., Oradell, N.J., 1995; and Drug Facts andComparisons, Inc., St. Louis, Mo., 1993. The precise dose to be used inthe formulation will also depend on the route of administration, and theseriousness of the disease or disorder, and should be decided by thephysician and the patient's circumstances.

The amount of nitric oxide donor in a pharmaceutical composition can bein amounts of about 0.1 to about 10 times the molar equivalent of theCOX-2 selective inhibitor. The usual daily doses of the COX-2 selectiveinhibitors are about 0.001 mg to about 140 mg/kg of body weight per day,preferably 0.005 mg to 30 mg/kg per day, or alternatively about 0.5 mgto about 7 g per patient per day. For example, inflammations may beeffectively treated by the administration of from about 0.01 mg to 50 mgof the compound per kilogram of body weight per day, or alternativelyabout 0.5 mg to about 3.5 g per patient per day. The compounds may beadministered on a regimen of up to 6 times per day, preferably 1 to 4times per day, and most preferably once per day. Effective doses may beextrapolated from dose-response curves derived from in vitro or animalmodel test systems and are in the same ranges or less than as describedfor the commercially available compounds in the Physician's DeskReference, supra.

The invention also provides pharmaceutical kits comprising one or morecontainers filled with one or more of the ingredients of thepharmaceutical compounds and/or compositions of the invention,including, at least, one or more of the novel COX-2 selectiveinhibitors, that is optionally nitrosated and/or nitrosylated, and oneor more of the NO donors described herein. Associated with such kits canbe additional therapeutic agents or compositions (e.g., steroids,NSAIDs, 5-lipoxygenase (5-LO) inhibitors, leukotriene B₄ (LTB₄) receptorantagonists and leukotriene A₄ (LTA₄) hydrolase inhibitors, 5-HTagonists, HMG-CoA inhibitors, H₂ antagonists, antineoplastic agents,antiplatelet agents, thrombin inhibitors, thromboxane inhibitors,decongestants, diuretics, sedating or non-sedating anti-histamines,inducible nitric oxide synthase inhibitors, opioids, analgesics,Helicobacter pylori inhibitors, proton pump inhibitors, isoprostaneinhibitors, and the like), devices for administering the compositions,and notices in the form prescribed by a governmental agency regulatingthe manufacture, use or sale of pharmaceuticals or biological productswhich reflects approval by the agency of manufacture, use or sale forhumans.

EXAMPLES

The following non-limiting examples further describe and enable one ofordinary skill in the art to make and use the invention. In each of theexamples, flash chromatography was performed on 40 micron silica gel(Baker).

Example 11-(1-Cyclooctyl-3-((nitrooxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene1a. N-(Azacyclooctylidenemethyl)(tert-butoxy)carboxamide

Cyclooctanone (5 g, 39.6 mmol) and t-butyl carbazate (5.24 g, 39.6 mmol)in methanol (140 mL) was stirred at room temperature for 1 hour. Thesolvent was evaporated and the resulting solid dried under vacuo to givea white solid in quantitative yield. Mp 133° C. ¹H NMR (300 MHz, CDCl₃)δ 7.45 (br s, 1H), 2.35-2.40 (m, 2H), 2.27-2.35 (m, 2H), 1.60-1.82 (m,4H), 1.51 (s, 9H), 1.32-1.58 (m, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 158.3,152.9, 80.8, 36.5, 28.4, 27.4, 27.3, 26.5, 25.4, 24.6, 24.5. Massspectrum (API-TIS) m/z 241 (MH⁺). Anal. calcd. for C₁₃H₂₄N₂O₂: C, 64.97;H, 10.07; N, 11.66. Found: C, 64.74; H, 9.98; N, 11.64.

1b. (tert-Butoxy)-N-(cyclooctylamino)carboxamide

Sodium cyanoborohydride (2.48 g, 39.6 mmol) was added portion-wise to asuspension of the product of Example 1a (9.5 g, 39.6 mmol) in 50% aceticacid (100 mL) at room temperature. The resultant clear solution wasstirred for 2 hours at room temperature. The reaction mixture wasneutralized with 1N NaOH, extracted with CH₂Cl₂, washed with saturatedNaHCO₃, dried, filtered and evaporated to give the title compound as acolorless oil in quantitative yield. The crude product was used withoutfurther purification.

1c. Cyclooctyl hydrazine trifluoroacetate

Trifluoroacetic acid (20 mL) was added drop-wise to a solution of theproduct of Example 1b (5.6 g, 36.9 mmol) in CH₂Cl₂ (20 mL). The reactionmixture was stirred at room temperature for 1 hour. The solvent wasevaporated to give the trifluoroacetate salt of the title compound as acolorless oil in quantitative yield. ¹H NMR (300 MHz, CDCl₃) δ 6.00-6.25(br s, 1H), 3.70-3.95 (br s, 1H), 2.95-3.13 (m, 1H), 1.53 (s, 9H),1.40-1.85 (m, 14H). ¹³C NMR (75 MHz, CDCl₃) δ 157.0, 80.4, 60.0, 30.4,28.5, 27.4, 25.7, 23.9. Mass spectrum (API-TIS) m/z 243 (MH⁺).

1d. Methyl (2Z)-2-hydroxy-4-(4-methylthiophenyl)-4-oxobut-2-enoate

Dimethyloxalate (26 g, 180.7 mmol) was added to a stirred suspension ofsodium methoxide (9.75 g, 180.7 mmol) in dry toluene (200 mL) at 0° C.The white suspension was stirred for 15 min at 0° C. A solution of4′-(methylthio)acetophenone (15 g, 90.4 mmol) in dry toluene (150 mL)was then added drop-wise over 15 minutes giving a yellow suspensionwhich was stirred for 2 hours at room temperature. The thick yellowsuspension was transferred to a 2 liter flask and stirred vigorouslywith 10% HCl (250 mL) and EtOAc (200 mL) to dissolve all the solidpresent. The organic layer was separated and the aqueous layer wasextracted with EtOAc (100 mL). The combined organic extracts were washedwith water (250 mL), dried over Na₂SO₄ and the solvent was evaporatedunder reduced pressure to give thick brown oil. The brown oil wasdissolved in CH₂Cl₂ (25 mL) and hexane (125 mL) and left in a freezer at−20° C. for 16 hours to give the title compound (18 g, 79% yield) asorange color solid. Mp 81° C. ¹H NMR (300 MHz, CDCl₃) δ 7.83 (d, J=8.6Hz, 2H), 7.23 (d, J=8.6 Hz, 2H), 6.97 (s, 1H), 3.89 (s, 3H), 2.47 (s,3H); ¹³C NMR (75 MHz, CDCl₃). Mass spectrum (API-TIS) m/z 253 (MH⁺).Anal. calcd. for C₁₂H₁₂O₄S: C, 57.13; H, 4.79; S, 12.71. Found: C,56.85; H, 4.76; S, 12.43.

1e. Methyl 1-cyclooctyl-5-(4-methylthiophenyl)pyrazol-3-carboxylate

A mixture of the product Example 1d (2 g, 7.9 mmol) and the product ofExample 1c (3.65 g, 10.3 mmol) in methanol (40 mL) was heated at 70° C.for 2 hours and cooled to room temperature. The mixture was made basicwith 5% Na₂CO₃ and extracted with EtOAc which was then washed withsaturated NaHCO₃ and water. The organic extracts were dried over Na₂SO₄and the solvent was evaporated under reduced pressure to give a thickoil, which was purified by chromatography over silica gel eluting with1:2 EtOAc:Hex to give the title compound as a colorless oil (2.8 g, 99%yield). ¹H NMR (300 MHz, CDCl₃) δ 7.34 (dd, J=1.7 and 6.4 Hz, 2H), 7.26(dd, J=1.9 and 4.7 Hz, 2H), 6.75 (s, 1H), 4.35-4.55 (m, 1H), 3.92 (s,3H), 2.54 (s, 3H), 2.20-2.38 (m, 2H), 1.15-1.90 (m, 12H); ¹³C NMR (75MHz, CDCl₃) δ 163.3, 143.5, 142.6, 140.3, 129.7, 126.7, 126.4, 108.8,60.4, 59.6, 52.1, 34.2, 30.3, 27.3, 26.5, 25.7, 24.8, 23.7, 15.5. Massspectrum (API-TIS) m/z 359 (MH⁺).

1f. (1-Cyclooctyl-5-(4-methylthiophenyl)pyrazol-3-yl)methan-1-ol

Lithium aluminum hydride (6.78 mL of 1M solution in THF, 0.26 g, 6.78mmol) was added drop-wise to a solution of the product of Example 1e(2.43 g, 6.78 mmol) in THF (40 mL) at 0° C. The yellow solution wasstirred at room temperature for 1 hour. Solid Na₂SO₄.10H₂O was addedportionwise to the reaction mixture at 0° C., followed by few drops ofwater and 0.1 N NaOH. The solid was filtered and washed with EtOAc. Theresidue, obtained after evaporation of the filtrate, was purified bychromatography over silica gel eluting with 1:1 EtOAc:Hex to give thetitle compound (1.64 g, 73% yield) as an oil. ¹H NMR (300 MHz, CDCl₃) δ7.32 (dd, J=2.0 and 6.6 Hz, 2H), 7.26 (dd, J=1.6 and 6.6 Hz, 2H), 6.19(s, 1H), 4.79 (bd, J=3.4 Hz, 2H), 4.27-4.40 (m, 1H), 2.58-2.72 (m, 1H),2.53 (s, 3H), 2.08-2.25 (m, 2H), 1.20-1.88 (m, 12H); ¹³C NMR (75 MHz,CDCl₃) δ 151.3, 143.1, 139.5, 129.5, 127.7, 126.4, 104.1, 59.3, 58.5,34.1, 26.6, 26.3, 24.8, 15.6. Mass spectrum (API-TIS) m/z 331 (MH⁺), 313(M-OH). Anal. calcd. for C₁₉H₂₀N₂OS: C, 69.05; H, 7.93; N, 8.48. Found:C, 68.81; H, 8.06; N, 8.59.

1g.1-(1-Cyclooctyl-3-(hydroxymethyl)pyrazol-5-yl)-4-methylsulfonyl)benzene

The product of Example 1f (1.54 g, 4.67 mmol) was dissolved in MeOH (90mL). OXONE® (5.74 g, 9.33 mmol) in water (20 mL) was added at roomtemperature. The reaction mixture was stirred for 1 hour and theresulting solid was removed by filtration. CH₂Cl₂ was added to thefiltrate, that was washed with saturated NaHCO₃, water, dried overNa₂SO₄, and filtered. The residue after evaporation of the solvent wasrecrystallized from CH₂Cl₂/EtOAc/Hexane to give the title compound aswhite needles (1.4 g, 83% yield). Mp 127-128° C. ¹H NMR (300 MHz, CDCl₃)δ 8.05 (d, J=8.3 Hz, 2H), 7.57 (d, J=8.3 Hz, 2H), 7.26 (s, 1H), 4.73 (d,J=5.7 Hz, 2H), 4.25-4.37 (m, 1H), 3.13 (s, 3H), 2.08-2.30 (m, 2H),1.22-1.92 (m, 12H); ¹³C NMR (75 MHz, CDCl₃) δ 151.7, 141.6, 140.5,136.8, 130.0, 128.0, 105.1, 59.2, 59.1, 44.6, 34.1, 26.7, 26.2, 24.8.Mass spectrum (API-TIS) m/z 363 (MH⁺). Anal. calcd. for C₁₉H₂₆N₂O₃S: C,62.96; H, 7.23; N, 7.73; S, 8.84. Found: C, 62.99; H, 7.30; N, 7.67; S,8.87.

1h.1-(1-Cyclooctyl-3-((nitrooxy)methyl)pyrazol-5-yl)-4-methylsulfonyl)benzene

The product of Example 1g (0.52 g, 1.43 mmol) in CHCl₃ was added to amixture of fuming HNO₃ (0.30 mL, 0.45 g, 7.13 mmol) and Ac₂O (1.1 mL,1.16 g, 11.4 mmol) at −10° C. and stirred at −10° C. for 20 minutes. Thereaction mixture was quenched with ice cold water and extracted withCH₂Cl₂. The extracts were washed with ice cold saturated NaHCO₃, water,dried over Na₂SO₄, filtered and the solvent evaporated under reducedpressure. The residue obtained was recrystallized from CH₂Cl₂/EtOAc/Hexto give the title compound as a white solid (0.36 g, 63% yield). Mp110-111° C. ¹H NMR (300 MHz, CDCl₃) δ 8.06 (dd, J=1.8 and 6.7 Hz, 2H),7.56 (dd, J=1.8 and 6.5 Hz, 2H), 6.38 (s, 1H), 5.50 (s, 2H), 4.27-4.40(m, 1H), 3.13 (s, 3H), 2.12-2.30 (m, 2H), 1.27-1.96 (m, 12H); ¹³C NMR(75 MHz, CDCl₃) δ 143.3, 141.9, 140.9, 136.2, 130.0, 128.1, 107.3, 68.8,59.5, 44.6, 33.9, 26.7, 26.1, 24.6. Mass spectrum (API-TIS) m/z 408(MH⁺). Anal. calcd. for C₁₉H₂₅N₃O₅S: C, 56.00; H, 6.18; N, 10.31; S,7.87. Found: C, 56.12; H, 6.30; N, 10.27; S, 7.84.

Example 21-(1-Cycloheptyl-3-((nitrooxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene2a. Methyl 1-cycloheptyl-5-(4-methylthiophenyl)pyrazol-3-carboxylate

The title compound was prepared from the product of Example 1d,(tert-butoxy)-N-(cycloheptylamino)carboxamide, TFA, using the procedurefor Example 1e. ¹H NMR (300 MHz, CDCl₃) δ 7.34 (d, J=8.4 Hz, 2H), 7.26(d, J=8.4 Hz, 2H), 7.65 (s, 1H), 4.29 (m, 1H), 3.93 (s, 3H), 2.54 (s,3H), 1.39-1.96 (m, 12H). Mass spectrum (API-TIS) m/z 345 (MH⁺).

2b. Methyl1-cycloheptyl-5-(4-(methylsulfonyl)phenyl)pyrazol-3-carboxylate

The product of Example 2a (150 mg, 0.44 mmol) was dissolved in CH₂Cl₂ (2mL) and cooled to 0° C. The oxidant, m-CPBA (240 mg, 0.96 mmol), wasadded and the cooling bath was removed. The reaction mixture was stirredat room temperature for 1 hour. The reaction mixture was diluted withEtOAc (15 mL), washed with 1N Na₂CO₃ (2×5) followed by brine (1×5),dried over Na₂SO₄, and concentrated. This gave a solid that wasrecrystallized from EtOAc (300 μL) and hexane (450 μL) to give the titlecompound (90 mg, 54% yield) as a white solid. Mp 115-117° C. ¹H NMR (300MHz, CDCl₃) δ 8.07 (d, J=8.0 Hz, 2H), 7.56 (d, J=8.0 Hz, 2H), 6.53 (s,1H), 4.25 (pentet, J=6.0 Hz, 1H), 3.93 (s, 3H), 3.13 (s, 3H), 1.40-2.32(m, 12). Mass spectrum (API-TIS) m/z 377 (MH⁺). Anal calcd. forC₁₉H₂₄N₂O₄S: C, 60.62; H, 6.43; N, 7.44. Found C, 60.43; H, 6.36; N,7.47.

2c.1-(1-Cycloheptyl-3-(hydroxymethyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene

The product of Example 2b (1.8 g, 4.9 mmol) was dissolved in THF (20 mL)and cooled to 0° C. Solid lithium aluminum hydride (280 mg, 7.5 mmol)was added all at one time. Stirring was continued at 0° C. for 30minutes followed by 30 minutes at room temperature. The reaction mixturewas cooled to 0° C. and excess lithium aluminum hydride was destroyed bythe sequential addition of H₂O (350 μL), 15% NaOH (350 μL), H₂O (1 mL).The precipitate that formed was removed by filtration through Celite,washed with EtOAc (2×25). The combined filtrates were dried over Na₂SO₄and concentrated. Trituration of the solid residue with hexane (6 mL)and EtOAc (3 mL) gave the title compound (1.0 g, 60% yield) as a whitesolid. Mp 116-118° C. ¹H NMR (300 MHz, CDCl₃) δ 8.04 (d, J=8.2 Hz, 2H),7.55 (d, J=8.2 Hz, 2H), 6.29 (s, 1H), 4.73 (d, J=5.6 Hz, 2H), 4.19(pentet, J=4.6 Hz, 1H), 3.12 (s, 3H), 1.26-2.24 (m, 12). Mass spectrum(API-TIS) m/z 349 (MH⁺). Anal calcd. for C₁₈H₂₄N₂O₃S: C, 62.04; H, 6.94;N, 8.04. Found C, 61.87; H, 6.94; N, 7.99.

2d.1-(1-Cycloheptyl-3-((nitrooxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene

Fuming nitric acid 90% (350 μL, 7.5 mmol) was added to acetic anhydride(1.1 mL, 12 mmol) and the mixture stirred at room temperature for 30minutes, it was then cooled to 0° C. and diluted with EtOAc (10 mL). Theproduct of Example 2c in EtOAc and the above mentioned mixture werestirred for 2 hours at 0° C. The reaction mixture was partitionedbetween EtOAc (20 mL) and saturated NaHCO₃ (20 mL) by stirring for 20minutes. The organic layer was removed and the aqueous layer wasextracted with EtOAc (40 mL). The combined organic layers were driedover Na₂SO₄ and concentrated. Trituration of the residue in hexane (1.6mL) and EtOAc (0.4 mL) gave the title compound (400 mg, 70% yield) as awhite solid. Mp 119-120° C. ¹H NMR (300 MHz, CDCl₃) δ 8.06 (d, J=8.3 Hz,2H), 7.55 (d, J=8.4 Hz, 2H), 6.38 (s, 1H), 5.50 (s, 2H), 4.22 (pentet,J=4.6 Hz, 1H), 3.13 (s, 3H), 1.42-2.20 (m, 12). Mass spectrum (API-TIS)m/z 394 (MH⁺). Anal calcd. for C₁₈H₂₃N₃O₅S: C, 54.95; H, 5.89; N, 10.68.Found C, 54.97; H, 5.99; N, 10.42.

Example 31-(1-Cyclohexyl-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-4-(nitrooxy)butan-1-one3a. Methyl(2Z)-2-hydroxy-4-(4-(methylsulfonyl)phenyl)-4-oxobut-2-enoate

OXONE® (4.39 g, 7.1 mmol) in water (14 mL) was added drop-wise to asolution of Example 1d (1.5 g, 6.0 mmol) in a mixture of MeOH (30 mL)and CH₂Cl₂ (2 mL) at 0° C. The resultant suspension was slowly allowedto warm to room temperature over a period of 1 hour. The solid wasfiltered off and the filtrate was diluted with CH₂Cl₂, washed withsaturated NaHCO₃, water, dried (Na₂SO₄) and filtered. The solvent wasevaporated to give the product (0.8 g, 47% yield). Mass spectrum(API-TIS) m/z 285 (MH⁺), 302 (MNH₄ ⁺).

3b. Methyl-1-cyclohexyl-5-(4-methylsulfonylphenyl)pyrazol-3-carboxylate

The product of Example 3a (7.4 g, 26 mmol) and cyclohexyl hydrazinehydrochloride (4.3 g, 29 mmol) were heated at reflux in MeOH (100 mL)for 6 hours. The reaction mixture was cooled to room temperature and afew drops of acetone was added to initiate crystallization. Theresulting thick slurry was diluted with H₂O (90 mL) and 1N HCl (20 mL),then cooled to −20° C. in a freezer. The solid was isolated byfiltration and washed with H₂O (2×50), dried in vacuo at roomtemperature to give the title compound (8.3 g, 88% yield) as a tansolid. Mp 108° C. ¹H NMR (300 MHz, CDCl₃) δ 8.09 (d, J=8.4 Hz, 2H), 7.59(d, J=8.4 Hz, 2H), 6.88 (s, 1H), 4.06-4.10 (m, 1H), 3.97 (s, 3H), 3.16(s, 3H), 1.26-2.19 (m, 10H). ¹³C NMR (75 MHz, CDCl₃) δ 162.5, 142.5,141.9, 140.8, 135.2, 129.7, 127.8, 109.3, 59.0, 51.8, 44.2, 33.1, 25.2,24.5. Mass spectrum (API-TIS) m/z 363 (MH⁺).

3c.(1-Cyclohexyl-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-N-methoxy-N-methylcarboxamide

Trimethylaluminum (5.52 mL of 2M solution in hexane, 0.80 g, 11.1 mmol)was added drop-wise to a suspension of dimethylhydroxylaminehydrochloride in CH₂Cl₂ (10 mL) at 0° C. The clear solution was stirredat 0° C. for 45 minutes and then at room temperature for 40 minutes. Tothis solution the product of Example 3b (2.06 g, 5.7 mmol) in CH₂Cl₂ (4mL) was added drop-wise. The stirring was continued for 2 hours at roomtemperature. The reaction mixture was cooled to 0° C. and 10% HCl wascarefully added drop-wise. The aqueous phase was extracted with EtOAc,washed with water, brine, dried over Na₂SO₄ and filtered. The residueobtained after evaporation of the solvent was dissolved in CH₂Cl₂,filtered through a silica gel pad and was washed with EtOAc. Thecombined filtrate and washings were evaporated to give the titlecompound (1.48 g, 67% yield) as a white solid. Mp 53° C. ¹H NMR (300MHz, CDCl₃) δ 8.28 (d, J=8.3 Hz, 2H), 7.58 (d, J=8.3 Hz, 2H), 6.81 (s,1H), 4.00-4.20 (m, 1H), 3.85 (s, 3H), 3.48 (br s, 3H), 3.13 (s, 3H),1.78-2.20 (m, 7H), 1.13-1.37 (m, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 144.6,141.3, 140.9, 136.0, 130.0, 128.1, 109.5, 61.7, 59.0, 44.6, 33.5, 25.6,25.1, 14.7, 14.2. Mass spectrum (API-TIS) m/z 392 (MH⁺). Anal. calcd.for C₁₉H₂₅N₃O₄S: C, 58.29; H, 6.44; N, 10.73. Found: C, 57.98; H, 6.45;N, 10.35.

3d.1-(1-Cyclohexyl-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-4-(1,1,2,2-tetramethyl-1-silapropoxy)butan-1-one

To a solution of the product of Example 3c (1.0 g, 2.56 mmol) in THF (20mL) was added drop-wise the Grignard reagent prepared from3-bromo-1-(1,1,2,2-tetramethyl-1-silapropoxy)propane (5 g, 19.8 mmol)and magnesium turnings (1.02 g, 42.5 mmol) in THF (50 mL) at 0° C. undernitrogen. The reaction mixture was gradually allowed to warm to roomtemperature. After all the starting material had been consumed,saturated aqueous NH₄Cl solution was added drop-wise at 0° C. Thereaction mixture was diluted with EtOAc and the layers were separated.The aqueous layer was extracted with EtOAc and the combined organiclayers were washed with water, dried (Na₂SO₄) and filtered. The residueobtained after evaporation of the solvent was purified by chromatographyover silica gel eluting first with 1:10 to 2:10, then with 1:2 to 1:1and lastly with 2:1 EtOAc:hexane to give the title compound (1.27 g, 98%yield) as a white solid. Mp 131-133° C. ¹H NMR (300 MHz, CDCl₃) δ 8.08(d, J=8.4 Hz, 2H), 7.58 (d, J=8.4 Hz, 2H), 6.82 (s, 1H), 3.95-4.25 (m,1H), 3.74 (t, J=6.3 Hz, 2H), 3.16 (s, 3H), 3.13 (t, J=7.4 Hz, 2H),1.80-2.20 (m, 7H and 2H), 1.22-1.40 (m, 3H), 0.91 (s, 9H), 0.08 (s, 6H);¹³C NMR (75 MHz, CDCl₃) δ 96.5, 150.3, 142.4, 141.0, 135.9, 130.0,128.1, 107.1, 62.7, 59.0, 44.6, 35.3, 33.4, 27.6, 26.1, 25.5, 25.1,18.5, −5.2. Mass spectrum (API-TIS) m/z 505 (MH⁺). Anal. calcd. forC₂₆H₄₀N₂O₄SSi: C, 61.87; H, 7.99; N, 5.55. Found: C, 61.81; H, 7.70; N,5.48.

3e.1-(1-Cyclohexyl-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-4-hydroxybutan-1-one

Tetrabutyl ammonium fluoride (2.57 mL of 1 M solution in THF, (0.67 g,2.57 mmol) was added drop-wise to a solution of the product of Example3d (1.04 g, 2.06 mmol) in THF (24 mL) at 0° C. The resultant solutionwas stirred at 0° C. for 2 hours and then at room temperature for 3hours. The residue obtained after evaporation of the solvent waspurified by chromatography over silica gel eluting with 1:1 to 2:1EtOAc:hexane to give an oil which was recrystallized fromCH₂Cl₂/EtOAc/Hexane to give the title compound (0.64 g, 79% yield). Mp112-114° C. ¹H NMR (300 MHz, CDCl₃) δ 8.07 (d, J=8.3 Hz, 2H), 7.57 (dd,J=1.7 and 6.7 Hz, 2H), 6.83 (s, 1H), 4.00-4.20 (m, 1H), 3.65-3.80 (m,2H), 3.19 (t, J=6.9 Hz, 2H), 3.14 (s, 3H), 2.32 (t, J=5.8 Hz, 1H), 2.03(p, J=6.8 Hz, 2H), 1.68-1.97 (m, 6H), 1.18-1.40 (m, 4H). ¹³C NMR (75MHz, CDCl₃) δ 196.9, 150.4, 142.7, 141.1, 135.7, 130.0, 128.2, 107.3,62.3, 59.2, 44.6, 35.4, 33.5, 27.8, 25.5, 25.1. Mass spectrum (API-TIS)m/z 391 (MH⁺), 373 (M-OH). Anal. calcd. for C₂₀H₂₆N₂O₄S: C, 61.52; H,6.71; N, 7.17. Found: C, 61.25; H, 6.66; N, 7.08.

3f.1-(1-Cyclohexyl-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-4-(nitrooxy)butan-1-one

The title compound was prepared as a white solid from the product ofExample 3e using the procedure for Example 1h. Mp 122-124° C. ¹H NMR(300 MHz, CDCl₃) δ 8.07 (d, J=8.2 Hz, 2H), 7.56 (d, J=8.2 Hz, 2H), 6.81(s, 1H), 4.59 (t, J=6.4 Hz, 2H), 4.04-4.09 (m, 1H), 3.21 (t, J=7.1 Hz,2H), 3.13 (s, 3H), 2.15-2.24 (m, 2H), 1.67-2.13 (m, 7H), 1.12-1.42 (m,3H); ¹³C NMR (75 MHz, CDCl₃) δ 194.7, 149.9, 142.6, 141.1, 135.7, 130.0,128.2, 107.2, 72.8, 59.2, 44.6, 34.5, 33.4, 25.5, 25.1, 21.5. Massspectrum (API-TIS) m/z 435 (MH⁺). Anal. calcd. for C₂₀H₂₅N₃O₆S: C,55.16; H, 5.79; N, 9.65. Found: C, 54.93; H, 5.62; N, 9.49.

Example 41-(3-((1Z)-4-(Nitrooxy)but-1-enyl)-1-cyclohexylpyrazol-5-yl)-4-(methylsulfonyl)benzene4a. Methyl-1-cyclohexyl-5-(4-methylthiophenyl)pyrazol-3-carboxylate

A mixture of the product of Example 1d (1.98 g, 7.8 mmol) andcyclohexylhydrazine hydrochloride (1.54 g, 10.2 mmol) in methanol (40mL) was heated at 70° C. for 3 hours and then cooled to roomtemperature. The mixture was made basic with 10% Na₂CO₃ and extractedwith EtOAc (3×25 mL). The organic extracts were dried over Na₂SO₄ andthe solvent was evaporated under reduced pressure to give a thick oil.The oil was dissolved in CH₂Cl₂ (4 mL) and hexane (20 mL) and left in afreezer at −10° C. for 16 hours to give the title compound (2.2 g, 85%yield) as a white solid. Mp 84° C. ¹H NMR (300 MHz, CDCl₃) δ 7.33 (d,J=8.3 Hz, 2H), 7.26 (d, J=8.3 Hz, 2H), 6.76 (s, 1H), 4.08-4.13 (m, 1H),3.93 (s, 3H), 2.54 (s, 3H), 2.07-2.20 (m, 2H), 1.80-1.95 (m, 4H),1.62-1.72 (m, 1H), 1.20-1.30 (m, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 163.1,143.6, 142.3, 140.1, 129.4, 126.4, 126.2, 108.8, 58.7, 51.9, 33.1, 25.5,24.8, 15.3. Mass spectrum (API-TIS), m/z 331 (MH⁺). Anal. calcd. forC₁₈H₂₂N₂O₂S: C, 65.43; H, 6.71; N, 8.48; S, 9.70. Found: C, 65.28; H,6.66; N, 8.47; S, 9.61.

4b. 1-Cyclohexyl-5-(4-methylthiophenyl)pyrazol-3-yl)methan-1-ol

A solution of lithium aluminum hydride (1 M in THF, 2 mL, 2 mmol) wasadded to a stirred solution of the product of Example 4a (0.7 g, 2.1mmol) in THF (15 mL) at 0° C. The resulting clear solution was stirredat room temperature for 1 hour. Solid Na₂SO₄.10H₂O (2 g) was added insmall portions with stirring until a thick precipitate formed. Methanolin CH₂Cl₂ (10%, 50 mL) was added and the mixture was filtered. The solidwas washed with additional methanol in CH₂Cl₂ (10%, 50 mL) and thecombined filtrates were evaporated to give the title compound (0.61 g,95% yield) as a white solid. Mp 97° C. ¹H NMR (300 MHz, CDCl₃) δ 7.31(d, J=8.3 Hz, 2H), 7.24 (d, J=8.3 Hz, 2H), 6.20 (s, 1H), 4.71 (d, J=4.8Hz, 2H), 4.00-4.15 (m, 1H), 2.53 (s, 3H), 1.65-2.10 (m, 7H), 1.15-1.30(m, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 151.0, 143.2, 139.3, 129.3, 127.5,126.3, 104.1, 59.0, 57.7, 33.2, 25.6, 25.1, 15.4. Mass spectrum(API-TIS) m/z 303 (MH⁺).

4c. Methyl-1-cyclohexyl-5-(4-methylthiophenyl)pyrazol-3-carboxyladehyde

To a stirred solution of oxalyl chloride (0.66 mL, 0.96 g, 6.1 mmol) inCH₂Cl₂ (2.5 mL) at −78° C. under nitrogen was added DMSO (1.08 mL, 15.2mmol) in CH₂Cl₂ (2 mL) drop-wise over a period of 20 min. To thissolution the product of Example 4b (1.84 g, 6.1 mmol) in CH₂Cl₂ (12 mL)was added drop-wise over a period of 40 minutes at −78° C. The mixturewas stirred at −78° C. for 1.5 hours. Triethylamine (4.25 mL, 3.08 g,30.5 mmol) in CH₂Cl₂ (2.6 mL) was then added drop-wise over a period of45 minutes at −78° C. The resultant mixture was stirred at 0° C. for 20minutes. To this mixture, water (2 mL) was added drop-wise followed byCH₂Cl₂ (50 mL). The organic layer was separated and the aqueous layerwas extracted with CH₂Cl₂. The combined organic extracts were washedwith 5% HCl, dried over Na₂SO₄ and filtered. The residue afterevaporation of the solvent was recrystallized from CH₂Cl₂/EtOAc/Hexaneto give the title compound (1.4 g, 77% yield) as a white solid. Mp 63°C. ¹H NMR (300 MHz, CDCl₃) δ 9.97 (s, 1H), 7.32 (d, J=8.3 Hz, 2H), 7.24(d, J=8.3 Hz, 2H), 6.71 (s, 1H), 4.00-4.18 (m, 1H), 2.52 (s, 3H),1.50-1.90 (m, 7H), 1.15-1.25 (m, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 186.8,150.4, 144.4, 140.4, 129.3, 126.2, 105.4, 58.7, 33.2, 25.5, 24.5, 15.2.mass spectrum (API-TIS) m/z 301 (MH⁺).

4d.1-((3Z)-4-(1-Cyclohexyl-5-(4-methylthiophenyl)pyrazol-3-yl)but-3-enyloxy)-1,1,2,2-tetramethyl-1-silapropane

n-Butyl lithium (2.5 M solution in hexane, 2.25 mL, 0.36 g, 5.6 mmol),was added drop-wise to solution of(3-((1,1-dimethylethyl)-dimethylsilyl)-oxy)propyl)-triphenylphosphoniumbromide (2.45 g, 4.76 mmol) in THF (13 mL) at −78° C. The resultantsolution was stirred at −78° C. for 1 hour. To this solution the productof Example 4c (1.3 g, 4.3 mmol) in THF (13 mL) was added drop-wise. Thereaction mixture was stirred at −78° C. for 1 hour. The reaction mixturewas gradually allowed to warm to room temperature and stirred for 24hours. Water was added and the reaction mixture extracted with EtOAc,which was then washed with water, dried over Na₂SO₄ and filtered. Theresidue obtained after evaporation of the solvent was purified bychromatography over silica gel eluting with 0.5:10 EtOAc:Hexane to givethe pure Z-isomer (1.2 g, 61% yield) as a colorless oil and minorE-isomer (0.1 g, 5% yield). Z-isomer: ¹H NMR (300 MHz, CDCl₃) δ 7.33 (d,J=8.4 Hz, 2H), 7.28 (d, J=8.5 Hz, 2H), 6.47 (d, J=11.7 Hz, 1H), 6.28 (s,1H), 5.65-5.77 (m, 1H), 3.98-4.12 (m, 1H), 3.76 (t, J=6.9 Hz, 2H), 2.72(q, J=6.1 Hz, 2H), 2.54 (s, 3H), 1.60-2.18 (m, 7H), 1.15-1.40 (m, 3H),0.90 (s, 9H), 0.07 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 148.4, 142.8,139.3, 129.5, 128.7, 127.8, 126.4, 122.7, 105.9, 62.9, 57.8, 33.5, 33.1,26.1, 25.8, 25.3, 18.5, 15.6, −5.0. Mass spectrum (API-TIS) m/z 457(MH⁺).

4e.1-(3-((1Z)-4-(Hydroxy)but-1-enyl)-1-cyclohexylpyrazol-5-yl-4-methylsulfonyl)benzene

The product of Example 4d (1.17 g, 2.6 mmol) was dissolved in MeOH (51mL). OXONE® (4.73 g, 7.7 mmol) in water (111 mL) was added at roomtemperature. The reaction mixture was stirred for 1 hour and thenfiltered to remove the solid. CH₂Cl₂ was added to the filtrate which waswashed with saturated NaHCO₃, water, dried over Na₂SO₄ and filtered. Theresidue after evaporation of the solvent was recrystallized fromCH₂Cl₂/EtOAc/Hexane to give the product (0.88 g, 92% yield) as a whitesolid. Mp 170-172° C. ¹H NMR (300 MHz, CDCl₃) δ 8.05 (d, J=8.3 Hz, 2H),7.56 (d, J=8.3 Hz, 2H), 6.50 (d, J=11.5 Hz, 1H), 6.27 (s, 1H), 5.80-5.94(m, 1H), 3.90-4.10 (m, 1H), 3.87 (q, J=5.7 Hz, 2H), 3.79 (t, J=4.7 Hz,1H), 3.13 (s, 3H), 2.75 (q, J=5.9 Hz, 2H), 1.62-2.18 (m, 7H), 1.18-1.40(m, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 148.1, 141.5, 140.7, 136.5, 130.4,129.9, 128.1, 123.1, 107.1, 62.6, 58.5, 44.6, 33.6, 32.4, 25.7, 25.1.mass spectrum (API-TIS) m/z 375 (MH⁺). Anal. calcd. for C₂₀H₂₆N₂O₃S: C,64.14; H, 7.00; N, 7.48; S, 8.56. Found: C, 63.89; H, 7.07; N, 7.40; S,8.60.

4f.1-(3-((1Z)-4-(Nitrooxy)but-1-enyl)-1-cyclohexylpyrazol-5-yl)-4-(methylsulfonyl)benzene

The title compound was prepared as a white crystalline solid from theproduct of Example 4e by following the procedure for Example 1h. Mp137-138° C. ¹H NMR (300 MHz, CDCl₃) δ 8.05 (dd, J=1.5 and 8.4 Hz, 2H),7.57 (dd, J=1.7 and 6.7 Hz, 2H), 6.48 (d, J=10.2 Hz, 1H), 6.27 (s, 1H),5.62-5.74 (m, 1H), 4.64 (t, J=6.9 Hz, 2H), 3.93-4.10 (m, 1H), 3.13 (s,3H), 3.00-305 (m, 2H), 1.78-2.14 (m, 6H), 1.62-1.77 (m, 1H), 1.19-1.38(m, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 148.0, 141.3, 140.6, 136.6, 129.9,128.1, 125.7, 124.1, 107.2, 72.7, 58.5, 44.6, 33.5, 27.3, 25.7, 25.2.Mass spectrum (API-TIS) m/z 420 (MH⁺). Anal. calcd. for C₂₀H₂₅N₃O₅S.¼mol H₂O: C, 56.66; H, 6.06; N, 9.91. Found: C, 56.80; H, 5.99; 9.85.

Example 54-(methylsulfonyl)-1-(3-((3-(nitrooxy)propoxy)methyl)-1-phenylpyrazol-5-yl)benzene5a. Methyl 5-(4-(methylsulfonyl)phenyl)-1-phenylpyrazol-3-carboxylate

The phenyl hydrazine hydrochloride (2.9 g, 20 mmol) and the product ofExample 3a (4.5 g, 16 mmol) were added to MeOH and the solution heatedat reflux for 4 hours. The reaction mixture was cooled to roomtemperature and H₂O was added until the solution became turbid and aprecipitate formed. The precipitate was isolated by filtration andwashed with H₂O (1×40). The solid was recrystallized from MeOH (2×300)to give the title compound (3 g, 50% yield) as a white solid. Mp190-193° C. ¹H NMR (300 MHz, CDCl₃) δ 7.89 (d, J=8.5 Hz, 2H), 7.34-7.43(m, 5H), 7.30-7.33 (m, 2H), 7.15 (s, 1H), 3.99 (s, 3H), 3.07 (s, 3H).Mass spectrum (API-TIS) m/z 357 (MH⁺). Anal calcd. for C₁₈H₁₆N₂O₄S: C,60.66; H, 4.53; N, 7.86. Found C, 60.60; H, 4.46; N, 7.77.

5b. 4-(3-(Hydroxymethyl)-1-phenylpyrazol-5-yl)-1-(methylsulfonyl)benzene

A flask was charged with lithium aluminum hydride (320 mg, 8.4 mmol) inTHF (8 mL) and cooled to 0° C. The product of Example 5a (1.85 mg, 5.2mmol) in THF (10 mL) was added slowly. The reaction mixture was stirredat 0° C. for 15 minutes then allowed to warm to room temperature whilestirring and then stirred for 3 hours at room temperature. The excesslithium aluminum hydride was destroyed by adding sequentially H₂O (500μL), 15% NaOH (500 μL), H₂O (1.5 mL). The precipitate that formed wasremoved by filtration through Celite, the filter cake was washed withEtOAc (2×20). The combined filtrates were dried over Na₂SO₄ andconcentrated. This gave the title compound (1.6 mg, 93% yield) as awhite solid. ¹H NMR (300 MHz, CDCl₃) δ 7.85 (d, J=8.7 Hz, 2H), 7.34-7.41(m, 5H), 7.23-7.27 (m, 2H), 6.62 (s, 1H), 4.79 (s, 2H), 3.06 (s, 3H).

5c. 4-(3-(Bromomethyl)-1-phenylpyrazol-5-yl)-1-(methylsulfonyl)benzene

The product of Example 5b (1.6 g, 4.9 mmol) was dissolved in CH₂Cl₂ (25mL) and cooled to 0° C. Phosphorous tribromide (470 μL, 4.9 mmol) wasadded and the mixture was stirred at room temperature for 2.5 hours. Thereaction mixture was diluted with CH₂Cl₂ and washed with H₂O (2×20) anddried over Na₂SO₄. Evaporation of the solvent gave a residue that waspurified chromatography over silica gel eluting with Hexane:EtOAc 1:1 togive the title compound (1.2 g, 63% yield). ¹H NMR (300 MHz, CDCl₃) δ7.87 (d, J=8.7 Hz, 2H), 7.36-7.43 (m, 5H), 7.24-7.28 (m, 2H), 6.68 (s,1H), 4.58 (s, 2H), 3.06 (s, 3H).

5d.4-(3-((3-Hydroxypropoxy)methyl)-1-phenylpyrazol-5-yl)-1-(methylsulfonyl)benzene

To a slurry of 95% NaH (210 mg, 8.4 mmol) in THF (15 mL) at 0° C. wasadded 3-benzyloxypropanol (850 μL, 5.6 mmol). The mixture was stirred atroom temperature for 40 minutes by which time effervescence had ceased.The product of Example 5c (2 mg, 5.1 mmol) in THF (10 mL) was added andthe reaction mixture was stirred at room temperature for 18 hours.Excess NaH was quenched with 1N HCl (40 mL), and the reaction mixturewas extracted with EtOAc (2×40). The combined extracts were washed withbrine, dried over Na₂SO₄, and concentrated. The residue was taken up inEtOH (30 mL) and TFA (250 μL) and the hydrogenation was performed using10% Pd/C (1 g) at 50 psi of hydrogen for 18 hours. The reaction mixturewas filtered through Celite to remove the catalyst and was washed withEtOAc (2×25). The combined filtrate was concentrated and redissolved inCHCl₃ (60 mL). The chloroform solution was washed with H₂O (2×30), driedover Na₂SO₄, and concentrated. Chromatography of the residue over silicagel eluting with EtOAc gave the title compound (600 mg, 30% yield). ¹HNMR (300 MHz, CDCl₃) δ 7.86 (d, J=8.6 Hz, 2H), 7.41 (d, J=8.6 Hz, 2H),7.25-7.38 (m, 5H), 6.63 (s, 1H), 4.65 (s, 2H), 3.81 (t, J=5.9 Hz, 2H),3.79 (t, J=5.9 Hz, 2H), 3.06 (s, 3H), 1.90 (pentet, J=5.7 Hz, 2H). Massspectrum (API-TIS) m/z 387 (MH⁺). Anal calcd. for C₂₀H₂₂N₂O₄S: C, 62.16;H, 5.74; N, 7.25. Found C, 62.39; H, 5.58; N, 7.16.

5e.4-(3-((3-(Nitrooxy)propoxy)methyl)-1-phenylpyrazol-5-yl)-1-(methylsulfonyl)benzene

Fuming HNO₃ (1.0 mL, 26 mmol) was cooled to 0° C. The product of Example5d (400 mg, 1 mmol) in CHCl₃ was added and the mixture stirred at 0° C.for 30 minutes. The reaction mixture was poured in to saturated aqueousNaHCO₃ (20 mL). The aqueous mixture was extracted with CHCl₃ (3×15). Thecombined extracts were dried over Na₂SO₄, and concentrated. The residuewas purified chromatography over silica gel eluting with Hexane:EtOAc1:1 to give the title compound (300 mg) as a clear oil. ¹H NMR (300 MHz,CDCl₃) δ 7.87 (d, J=8.3 Hz, 2H), 7.42 (d, J=8.3 Hz, 2H), 7.25-7.39 (m,5H), 6.63 (s, 1H), 4.63 (s, 2H), 4.61 (t, J=6.4 Hz, 2H), 3.69 (t, J=5.9Hz, 2H), 3.06 (s, 3H), 2.06 (pentet, J=6.2 Hz, 2H). Mass spectrum(API-TIS) m/z 432 (MH⁺). Anal calcd. for C₂₀H₂₁N₃O₆S: C, 55.68; H,4.914; N, 9.74. Found C, 54.72; H, 4.58; N, 9.46.

Example 61-(3-(Difluoro(3-(nitrooxy)propoxy)methyl)-1-phenylpyrazol-5-yl)-4-(methylsulfonyl)benzene6a. (4-(Methylsulfonyl)phenyl)-1-phenylpyrazol-3-carboxylic acid

The product of Example 5a (1.0 g, 2.8 mmol) and NaOH (130 mg, 3.2 mmol)in MeOH (10 mL) were heated to reflux for 8 hours. The reaction mixturewas cooled to room temperature and partitioned between EtOAc (30 mL) and0.5 N HCl (30 mL). The aqueous layer was extracted with EtOAc (2×15).The combined organic layers were washed with brine, dried over Na₂SO₄,and concentrated. This gave the title compound (1 g, 100% yield) as asolid. Mp 207-208° C. ¹H NMR (300 MHz, CDCl₃) δ 7.90 (d, J=8.1 Hz, 2H),7.40-7.44 (m, 5H), 7.26-7.35 (m, 2H), 7.20 (s, 1H), 3.06 (s, 3H).

6b. 3-(Phenylmethoxy)propyl5-(4-(methylsulfonyl)phenyl)-1-phenylpyrazol-3-carboxylate

The product of Example 6a. (7.5 g, 22 mmol) was dissolved in toluene (50mL) containing DMF (25 μL). Oxalyl chloride (2M/CH₂Cl₂, 22 mL, 44 mmol)was added drop-wise. The reaction mixture was allowed to stir at roomtemperature for 1.5 hours, then concentrated to thick oil. A solution ofbenzyloxypropanol (3.6 mL, 22 mmol) and pyridine (1.7 mL, 22 mmol) inCH₂Cl₂ (40 mL) was prepared and cooled to 0° C. The acid chlorideprepared above was dissolved in CH₂Cl₂ (10 mL) and added drop-wise tothe alcohol/pyridine mixture. The reaction mixture was allowed to warmto room temperature and stirred for 18 hours. The reaction mixture wasdiluted with CH₂Cl₂ (60 mL); washed with 1N HCl, saturated NaHCO₃, andH₂O (1×30); dried over Na₂SO₄; and concentrated to give the titlecompound (10.3 g, 95% yield) as an oil. ¹H NMR (300 MHz, CDCl₃) δ 7.88(d, J=8.1 Hz, 2H), 7.39-7.42 (m, 6H), 7.29-7.34 (m, 8H), 7.09 (s, 1H),4.53 (t, J=6.6 Hz, 2H), 4.53, (s, 2H), 3.65 (t, J=6.3 Hz, 2H), 3.07 (s,3H). 1.88 (pentet, J=6.3 Hz, 2H).

6c.1-(Methylsulfonyl)-4-(1-phenyl-3-((3-(phenylmethoxy)propoxy)thioxomethyl)pyrazol-5-yl)benzene

The product of Example 6b (10.3 g, 21 mmol) and Lawesson's reagent (32g, 80 mmol) were heated to reflux in toluene (120 mL) for 5 days. As thereaction mixture was cooled to 0° C. a precipitate formed. The solid wasremoved by filtration and the filtrate was concentrated to a heavy oil.The oil was triturated with Hexane:EtOAc 1:1 (100 mL). A secondprecipitate formed which was also removed by filtration and the filtratewas concentrated to an oil. The oily residue was filtered through silicagel eluting with CHCl₃ to 5% MeOH/CHCl₃ to give the title compound (3.8g, 36% yield). ¹H NMR (300 MHz, CDCl₃) δ 7.88 (d, J=8.1 Hz, 2H),7.39-7.42 (m, 6H), 7.26-7.34 (m, 8H), 7.09 (s, 1H), 4.87 (t, J=6.6 Hz,2H), 4.54, (s, 2H), 3.68 (t, J=5.7 Hz, 2H), 3.07 (s, 3H). 2.25 (pentet,J=6.0 Hz, 2H). Mass spectrum (API-TIS) m/z 507 (MH⁺).

6d.4-(3-(Difluoro(3-(phenylmethoxy)propoxy)methyl)-1-phenylpyrazol-5-yl)-1-(methylsulfonyl)benzene

The product of Example 6c (3.8 g, 7.5 mmol) and SbCl₃ (90 mg, 0.4 mmol)were dissolved in CH₂Cl₂ (40 mL) and cooled to 0° C.(Bis(2-methoxyethyl)amino)sulfur trifluoride (2.1 mL, 11.3 mmol) wasadded and the mixture was allowed to warm to room temperature withstirring for 3 hours. The reaction mixture was cooled to 0° C. andexcess reagent was quenched with saturated aqueous NaHCO₃. Addition ofNaHCO₃ (25 mL) was drop-wise until effervescence subsided then morerapid. The aqueous layer was separated and extracted with CH₂Cl₂. Thecombined organic layers were washed with 1N HCl and H₂O, dried overNa₂SO₄, and concentrated. The residue was purified by chromatographyover silica gel eluting with Hexane:EtOAc 1:1 to give the title compound(2.4 g, 62% yield). ¹H NMR (300 MHz, CDCl₃) δ 7.87 (d, J=8.4 Hz, 2H),7.25-7.42 (m, 12H), 6.77 (s, 1H), 4.53, (s, 2H), 4.24 (t, J=6.3 Hz, 2H),3.64 (t, J=6.3 Hz, 2H), 3.06 (s, 3H). 2.06 (pentet, J=6.3 Hz, 2H). Massspectrum (API-TIS) m/z 513 (MH⁺).

6e.1-(3-(Difluoro(3-hydroxypropoxy)methyl)-1-phenylpyrazol-5-yl)-4-(methylsulfonyl)benzene

The product of Example 6d (1.05 g, 2.05 mmol) and NaIO₄ (2.7 g, 12.3mmol) were taken up in a biphasic mixture of CCl₄ (20 mL), CH₃CN (20mL), and H₂O (30 mL). Ruthenium chloride (20 mg, 0.1 mmol) was added tothe mixture which was stirred at room temperature for 18 hours. Thereaction mixture was transferred to a separatory funnel with CHCl₃ (20mL) and saturated with NaCl. The organic layer was separated and theaqueous layer was extracted with CHCl₃ (3×25). The combined organicextracts were dried over Na₂SO₄ and concentrated. The residue was takenup in MeOH (20 mL) containing NaOH (200 mg, mmol) and stirred at roomtemperature for 5 hours. The MeOH was evaporated and replaced with H₂O(100 mL). The aqueous mixture was extracted with EtOAc (4×25). Thecombined organic extracts were washed with H₂O (2×25) and brine (1×25),dried over Na₂SO₄, and concentrated. The residue was purified bychromatography over silica gel eluting with Hexane:EtOAc 1:2 to give thetitle compound (390 mg, 50% yield) as a clear oil. ¹H NMR (300 MHz,CDCl₃) δ 7.87 (d, J=8.5 Hz, 2H), 7.38-7.43 (m, 5H), 7.27-7.37 (m, 2H),6.80 (s, 1H), 4.25 (t, J=6.1 Hz, 2H), 3.84 (t, J=5.9 Hz, 2H), 3.06 (s,3H). 2.0 (pentet, J=6.3 Hz, 2H). Mass spectrum (API-TIS) m/z 423 (MH⁺).Anal cald for C₂₀H₂₀F₂N₂O₄S: C, 56.86; H, 4.77; N, 6.63. Found C, 56.60;H, 4.54; N, 6.40.

6f.1-(3-(Difluoro(3-(nitrooxy)propoxy)methyl)-1-phenylpyrazol-5-yl)-4-(methylsulfonyl)benzeneAcetyl nitrate was prepared by addition of AgNO₃ (250 mg, 1.5 mmol) toAcCl (110 μL, 1.5 mmol) in CH₃CN (3 mL) and stirring at room temperaturefor 15 minutes. The AgCl precipitate was removed by filtration through acotton plug. A 2 mL portion of the filtered AcONO₂ solution was added tothe product of Example 6e in CH₃CN (6 mL), and stirred at roomtemperature for 2 hours. The reaction mixture was diluted withHexane:EtOAc 1:1 (60 mL). The organic mixture was extracted with satdNaHCO₃ (1×25) and brine (1×25), dried over Na₂SO₄, and concentrated. Theresidue was purified by chromatography over silica gel eluting withHexane:EtOAc 3:2 to give the title compound (100 mg, 36% yield) as anoil along with 3-(nitrooxy)propyl5-(4-(methylsulfonyl)phenyl)-1-phenylpyrazol-3-carboxylate (150 mg, 54%yield). ¹H NMR (300 MHz, CDCl₃) δ 7.88 (d, J=8.5 Hz, 2H), 7.38-7.44 (m,5H), 7.27-7.33 (m, 2H), 6.80 (s, 1H), 4.64 (t, J=6.3 Hz, 2H), 4.22 (t,J=6.0 Hz, 2H), 3.06 (s, 3H). 2.18 (pentet, J=6.2 Hz, 2H). Mass spectrum(API-TIS) m/z 468 (MH⁺). Example 71-(1-(4-Chlorophenyl)-3-((3-nitrooxy)propoxy)methyl)pyrazol-5-yl)-4-methylsulfonyl)benzene7a. Methyl1-(4-chlorophenyl)-5-(4-(methylsulfonyl)phenyl)pyrazol-3-carboxylate

A mixture of the product of Example 3a (5.0 g, 17.6 mmol) and4-chlorophenylhydrazine hydrochloride (3.46 g, 19.35 mmol) in MeOH (100mL) was heated at 70° C. for 18 hours and then cooled to roomtemperature. The solvent was removed and the residue was redissolved inCH₂Cl₂. The organic solution was washed with water and brine, and driedover magnesium sulfate. Evaporation of solvent provided a solid, whichwas recrystallized from CH₂Cl₂/Hexane to give the title compound as apale yellow solid (4.27 g, 62% yield). Mp 169-171° C. ¹H NMR (300 MHz,CDCl₃) δ 7.93 (d, J=8.4 Hz, 2H), 7.44 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.7Hz, 2H), 7.27 (d, J=8.7 Hz, 2H), 7.15 (s, 1H), 3.40 (s, 3H), 3.09 (s,3H). Mass spectrum (API-TIS) m/z 319 (MH⁺). Anal. calcd. forC₁₈H₁₅ClN₂O₄S: C, 55.32; H, 3.87; N, 7.17. Found: C, 55.27; H, 3.69; N,7.14.

7b.1-(1-(4-Chlorophenyl)-3-(hydroxymethyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene

The title compound (2.5 g, 61% yield) was prepared from the product ofExample 7a by following the procedure for Example 5b. Mp 96-100° C. ¹HNMR (300 MHz, CDCl₃) δ 7.89 (d, J=8.2 Hz, 2H), 7.41 (d, J=8.2 Hz, 2H),7.34 (d, J=8.6 Hz, 2H), 7.20 (d, 8.6, J=8.63 Hz, 2H), 6.62 (s, 1H), 4.80(d, J=5.7 Hz, 2H), 3.07 (s, 3H), 2.07 (br s, 1H). Mass spectrum(API-TIS) m/z 363 (MH⁺).

7c.1-(3-(Bromomethyl)-1-(4-chlorophenyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene

The title compound (2.1 g, 96% yield) was prepared from the product ofExample 7b by following the procedure for Example 5c. Mp 60-64° C. ¹HNMR (300 MHz, CDCl₃) δ 7.90 (d, J=8.5 Hz, 2H), 7.42 (d, J=8.5 Hz, 2H),7.36 (d, J=8.8 Hz, 2H), 7.21 (d, J=8.8 Hz, 2H), δ 6.68 (s, 1H), 4.56 (s,2H), 3.07 (s, 3H). Mass spectrum (API-TIS) m/z 426 (MH⁺).

7d.1-(1-(4-Chlorophenyl)-3-((3-hydroxypropoxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene

The title compound (531.4 mg, 57% yield) was prepared from the productof Example 7c by following the procedure for Example 5d except3-benzyloxy propanol was substituted for 2-benzyloxy ethanol. ¹H NMR(300 MHz, CDCl₃) δ 7.87 (d, J=8.4 Hz, 2H), 7.41 (d, J=8.4 Hz, 2H), 7.34(d, J=8.7 Hz, 2H), 7.20 (d, J=8.7 Hz, 2H), 6.61 (s, 1H), 4.64 (d, J=4.1Hz, 2H), 3.80 (t, J=5.7 Hz, 2H), 3.78 (t, J=5.7 Hz, 2H), 3.07 (s, 3H),1.89 (q, J=5.7 Hz, 2H). Mass spectrum (API-TIS) m/z 421 (MH⁺).

7e.1-(1-(4-Chlorophenyl)-3-((3-(nitrooxy)propoxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene

The title compound (35.0 mg, 39% yield) was prepared from the product ofExample 7d by following the procedure for Example 5e. ¹H NMR (300 MHz,CDCl₃) δ 7.89 (d, J=8.3 Hz, 2H), 7.41 (d, J=8.3 Hz, 2H), 7.34 (d, J=8.7Hz, 2H), 7.20 (d, J=8.7 Hz, 2H), 6.62 (s, 1H), 4.60 (s, 2H), 4.59 (t,J=6.1 Hz, 2H), 3.67 (t, J=6.1 Hz, 2H), 3.07 (s, 3H), 2.04 (q, J=6.1 Hz,2H). Mass spectrum (API-TIS) m/z 466 (MH⁺).

Example 81-(1-(4-Methylphenyl)-3-((3-nitrooxy)propoxy)methyl)pyrazol-5-yl)-4-methylsulfonyl)benzene8a. Methyl1-(4-methylphenyl)-5-(4-(methylsulfonyl)phenyl)pyrazol-3-carboxylate

The title compound was prepared from the product of Example 3a (5.0 g,17.6 mmol) and 4-methylphenylhydrazine hydrochloride (3.63 g, 22.9 mmol)in methanol (120 mL) was heated at 70° C. for 18 hours and cooled toroom temperature. The solvent was removed by rotary evaporation, and theresidue was redissolved in methylene chloride. The organic solution waswashed with water and brine, and dried over magnesium sulfate.Evaporation of solvent provided a solid, which was shown by NMR to be amixture of regioisomers. The crude product was purified bychromatography over silica gel, eluting with 50% ethyl acetate:hexane,to 100% ethyl acetate (gradient). The slower eluting compound wasrecrystallized from CH₂Cl₂/hexane to give the title compound (4.3 g, 66%yield) as a white solid. Mp 173-175° C. ¹H NMR (300 MHz, CDCl₃) δ7.87(d, J=8.3 Hz, 2H), 7.41 (d, J=8.3 Hz, 2H), 7.17 (s, 4H), 7.13 (s, 1H),3.97 (s, 3H), 3.06 (s, 3H), 2.38 (s, 3H). Mass spectrum (API-TIS) m/z371 (MH⁺). Anal. calcd. for C₁₉H₁₈N₂O₄S: C, 61.61; H, 4.90; N, 7.56.Found: C, 61.62; H, 4.77; N, 7.61.

8b.1-(3-(Hydroxymethyl)-1-(4-methylphenyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene

The title compound (2.7 g, 80% yield) was prepared from the product ofExample 8a by following the procedure for Example 5b. ¹H NMR (300 MHz,CDCl₃) δ 7.86 (d, J=8.5 Hz, 2H), 7.41 (d, J=8.5 Hz, 2H), 7.18-7.11 (m,4H), 6.61 (s, 1H), 4.80 (d, J=5.9 Hz, 2H), 3.08 (s, 3H), 2.38 (s, 3H).Mass spectrum (API-TIS) m/z 342 (MH⁺)

8c.1-(3-(Bromomethyl)-1-(4-methylphenyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene

The title compound (2.7 g, 86% yield) was prepared from the product ofExample 8b by following the procedure for Example 5c. ¹H NMR (300 MHz,CDCl₃) δ 7.87 (d, J=8.6 Hz, 2H), 7.41 (d, J=8.6 Hz, 2H), 7.18-7.12 (m,4H), 6.67 (s, 1H), 4.58 (s, 2H), 3.06 (s, 3H), 2.38 (s, 3H). Massspectrum (API-TIS) m/z 374 (MH⁺)

8d.1-(3-((3-Hydroxypropoxy)methyl)-1-(4-methylphenyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene

The title compound (2.7 g, 80% yield) was prepared from the product ofExample 8c by following the procedure for Example 5d. (910 mg, 83%yield). ¹H NMR (300 MHz, CDCl₃) δ 7.85 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.4Hz, 2H), 7.17-7.10 (m, 4H), 6.59 (s, 1H), 4.63 (s, 2H), 3.79 (t, J=5.7Hz, 2H), 3.78 (t, J=5.7 Hz, 2H), 3.05 (s, 3H), 2.36 (s, 3H), 1.87 (q,J=5.7 Hz, 2H). Mass spectrum (API-TIS) m/z 401 (MH⁺)

8e.1-(1-(4-methylphenyl)-3-((3-(nitrooxy)propoxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene

The title compound (460 mg, 64% yield) was prepared from the product ofExample 8d by following the procedure for Example 5e. ¹H NMR (300 MHz,CDCl₃) δ 7.86 (d, J=8.5 Hz, 2H), 7.41 (d, J=8.5 Hz, 2H), 7.18-7.11 (m,4H), 6.61 (s, 1H), 4.61 (s, 2H), 4.60 (t, J=6.1 Hz, 2H), 3.68 (t, J=6.1Hz, 2H), 3.07 (s, 3H), 2.37 (s, 3H), 2.04 (q, J=6.1 Hz, 2H). Massspectrum (API-TIS) m/z 446 (MH⁺)

Example 94-(Methylsulfonyl)-1-(3-((3-nitrooxy)propoxy)methyl)-1-(4-trifluoromethyl)phenyl)pyrazol-5-yl)benzene9a. Methyl5-(4-(methylsulfonyl)phenyl)-1-(4-(trifluoromethyl)phenyl)pyrazol-3-carboxylate

The title compound was prepared from the product of Example 3a (5.0 g,17.6 mmol) and 4-(trifluoromethyl)phenylhydrazine hydrochloride (4.03 g,22.9 mmol) in acetic acid (120 mL) was heated at 70° C. for 18 hours andthen cooled to room temperature. The solvent was removed by rotaryevaporation, and the residue was redissolved in CH₂Cl₂. The organicsolution was washed with water and brine, and dried over magnesiumsulfate. Evaporation of solvent provided a solid, which wasrecrystallized from CH₂Cl₂/hexane to give the title compound as paleyellow needles (5.38 g, 72% yield). Mp 204-207° C. ¹H NMR (300 MHz,CDCl₃) δ 7.95 (d, J=8.4 Hz, 2H), 7.68 (d, J=8.5 Hz, 2H), 7.48 (d, J=8.5Hz, 2H), 7.45 (d, J=8.4 Hz, 2H), 7.17 (s, 1H), 4.01 (s, 3H), 3.10 (s,3H). Mass spectrum (API-TIS) m/z 425 (MH⁺), 442 (M+18⁺). Anal. calcd.for C₁₉H₁₅F₃N₂O₄S: C, 53.77; H, 3.56; N, 6.60. Found: C, 53.72; H, 3.52;N, 6.54.

9b.1-(3-(Hydroxymethyl)-1-(4-(trifluoromethyl)phenyl)pyrazol-5-yl-4-(methylsulfonyl)benzene

The title compound (4.0 g, 86% yield) was prepared from the product ofExample 9a by following the procedure for Example 5b. ¹H NMR (300 MHz,CDCl₃) δ 7.92 (d, J=8.4 Hz, 2H), 7.64 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.5Hz, 2H), 7.39 (d, J=8.5 Hz, 2H), 6.65 (s, 1H), 4.81 (s, 2H), 3.08 (s,3H). Mass spectrum (API-TIS) m/z 397 (MH⁺).

9c.1-(3-(Bromomethyl)-1-(4-(trifluoromethyl)phenyl)pyrazol-5-yl-4-(methylsulfonyl)benzene

The title compound (3.7 g, 80% yield) was prepared from the product ofExample 9b by following the procedure for Example 5c. ¹H NMR (300 MHz,CDCl₃) δ 7.93 (d, J=8.4 Hz, 2H), 7.64 (d, J=8.4 Hz, 2H), 7.44-7.36 (m,4H), 6.69 (s, 1H), 4.56 (s, 2H), 3.08 (s, 3H). Mass spectrum (API-TIS)m/z 459 (MH⁺).

9d.1-(3-((3-Hydroxypropoxy)methyl)-1-(4-(trifluoromethyl)phenyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene

The title compound (920 mg, 79% yield) was prepared from the product ofExample 9a by following the procedure for Example 5d except 2-benzyloxyethanol was used instead of 3-benzyloxy propanol. ¹H NMR (300 MHz,CDCl₃) δ 7.92 (d, J=8.4 Hz, 2H), 7.63 (d, J=8.4 Hz, 2H), 7.44-7.28 (m,4H), 6.64 (s, 1H), 4.64 (s, 2H), 3.81 (t, J=5.8 Hz, 2H), 3.79 (t, J=5.8Hz, 2H), 3.08 (s, 3H), 1.90 (q, J=5.8 Hz, 2H). Mass spectrum (API-TIS)m/z 455 (MH⁺).

9e.4-(Methylsulfonyl)-1-(3-((3-(nitrooxy)propoxy)methyl)-1-(4-(trifluoromethyl)phenyl)pyrazol-5-yl)benzene

The title compound (189.3 mg, 22% yield) was prepared from the productof Example 9d by following the procedure for Example 5e. ¹H NMR (300MHz, CDCl₃) δ 7.91 (d, J=8.5 Hz, 2H), 7.63 (d, J=8.5 Hz, 2H), 7.44-7.38(m, 4H), 6.64 (s, 1H), 4.61 (s, 2H), 4.59 (t, J=5.9 Hz, 2H), 3.68 (t,J=5.8 Hz, 2H), 3.07 (s, 3H), 2.04 (q, J=5.9 Hz, 2H). Mass spectrum(API-TIS) m/z 500 (MH⁺)

Example 101-(1-(4-Methoxy-3-nitrophenyl)-3-((3-nitrooxy)propoxy)methyl)pyrazol-5-yl)-4-methylsulfonyl)benzene10a. Methyl1-(4-methoxyphenyl)-5-(4-(methylsulfonyl)phenyl)pyrazol-3-carboxylate

The title compound was prepared as a white solid (3.99 g, 59% yield) byfollowing the procedure for Example 8a. with a mixture of the product ofExample 3a (5.0 g, 17.6 mmol) and 4-methoxyphenyl hydrazinehydrochloride (4.00 g, 22.9 mmol) in methanol (150 mL). Mp 136-138° C.¹H NMR (300 MHz, CDCl₃) δ 7.88 (d, J=8.5 Hz, 2H), 7.41 (d, J=8.5 Hz,2H), 7.22 (d, J=8.9 Hz, 2H), 7.13 (s, 1H), 6.89 (d, J=8.9 Hz, 2H), 3.98(s, 3H), 3.84 (s, 3H), 3.07 (s, 3H). Mass spectrum (API-TIS) m/z 387(MH⁺); Anal. calcd. for C₁₉H₁₈N₂O₅S: C, 59.06; H, 4.70; N, 7.25. Found:C, 58.84; H, 4.63; N, 7.26.

10b.1-(3-(Hydroxymethyl)-1-(4-methoxyphenyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene

The title compound (3.2 g, 97% yield) was prepared from the product ofExample 10a by following the procedure for Example 5b. ¹H NMR (300 MHz,CDCl₃) δ 7.84 (d, J=8.4 Hz, 2H), 7.38 (d, J=8.4 Hz, 2H), 7.15 (d, J=8.9Hz, 2H), 6.86 (d, J=8.9 Hz, 2H), 6.59 (s, 1H), 4.75 (s, 2H), 3.80 (s,3H), 3.04 (s, 3H). Mass spectrum (API-TIS) m/z 359 (MH⁺).

10c.1-(3-(Bromomethyl)-1-(4-methoxyphenyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene

The title compound (1.7 g, 46% yield) was prepared from the product ofExample 10b by following the procedure for Example 5c. ¹H NMR (300 MHz,CDCl₃) δ 7.85 (d, J=8.4 Hz, 2H), 7.38 (d, J=8.4 Hz, 2H), 7.18 (d, J=8.9Hz, 2H), 6.88 (d, J=8.9 Hz, 2H), 6.61 (s, 1H), 4.56 (s, 2H), 3.80 (s,3H), 3.05 (s, 3H). Mass spectrum (API-TIS) m/z 422 (MH⁺).

10d.1-(3-((3-Hydroxypropoxy)methyl)-1-(4-methoxyphenyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene

The title compound (770 mg, 47% yield) was prepared from the product ofExample 10c by following the procedure for Example 5d except 2-benzyloxyethanol was used instead of 3-benzyloxy propanol. ¹H NMR (300 MHz,CDCl₃) δ 7.84 (d, J=8.5 Hz, 2H), 7.39 (d, J=8.5 Hz, 2H), 7.17 (d, J=8.9Hz, 2H), 6.87 (d, J=8.9 Hz, 2H), 6.59 (s, 1H), 4.62 (s, 2H), 3.81 (s,3H), 3.80-3.75 (m, 4H), 3.04 (s, 3H), 1.88 (q, J=5.7 Hz, 2H). Massspectrum (API-TIS) m/z 417 (MH⁺).

10e.1-(1-(4-Methoxy-3-nitrophenyl)-3-((3-(nitrooxy)propoxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene

The title compound (120.5 mg, 72% yield) was prepared from the productof Example 10d by following the procedure for Example 5e. ¹H NMR (300MHz, CDCl₃) δ 7.90 (d, J=8.3 Hz, 2H), 7.83 (d, J=2.7 Hz, 1H), 7.43 (d,J=8.3 Hz, 2H), 7.36 (dd, J=2.7 Hz, 1H), 7.05 (d, J=9.0 Hz, 1H), 6.62 (s,1H), 4.59 (s, 2H), 4.58 (t, J=6.0, 2H), 3.96 (s, 3H), 3.66 (t, J=6.0,2H), 3.06 (s, 3H), 2.03 (q, J=6.0 Hz, 2H). Mass spectrum (API-TIS) m/z507 (MH⁺)

Example 111-(3-((1Z)-4-(Nitrooxy)but-1-enyl)-1-phenylpyrazol-5-yl)-4-(methylsulfonyl)benzeneand1-(3-((1E)-4-(Nitrooxy)but-1-enyl)-1-phenylpyrazol-5-yl)-4-(methylsulfonyl)benzene11a. Methyl 5-(4-methylthiophenyl)-1-phenylpyrazol-3-carboxylate

A mixture of the product of Example 1d (10 g, 39.6 mmol) andphenylhydrazine hydrochloride (7.45 g, 51.6 mmol) in methanol (200 mL)was heated at 70° C. for 5 hours and cooled to room temperature. Themixture was made basic with 10% Na₂CO₃ and extracted with EtOAc (3×25mL). The organic extracts were dried over Na₂SO₄ and filtered. Theresidue, after evaporation of the solvent, was recrystallized fromCH₂Cl₂/EtOAc/hexane to give the title compound (8.8 g, 68% yield) as awhite solid. Mp 94-96° C. ¹H NMR (300 MHz, CDCl₃) δ 7.30-7.41 (m, 5H),7.17 (d, J=8.8 Hz, 2H), 7.12 (d, J=8.2 Hz, 2H), 7.03 (s, 1H), 3.97 (s,3H), 2.48 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 162.9, 144.4, 144.1, 140.1,139.6, 129.2, 129.1, 128.5, 126.0, 125.9, 125.8, 109.8, 52.2, 15.3. Massspectrum (API-TIS) m/z 325 (MH⁺). Anal. Calcd. for C₁₈H₁₆N₂O₂S: C,66.65; H, 4.97; N, 8.64. Found: C, 66.45; H, 4.92; N, 8.83.

11b. (5-(4-methylthiophenyl)-1-phenylpyrazol-3-yl)-methanol

The title compound was prepared as a white solid from the product ofExample 1f by following the procedure for Example 1f. Mp 105-106° C. ¹HNMR (300 MHz, CDCl₃) δ 7.26-7.39 (m, 5H), 7.09-7.18 (m, 4H), 6.49 (s,1H), 4.78 (d, J=5.9 Hz, 2H), 2.47 (s, 3H), 2.26 (t, J=6.0 Hz, 1H); ¹³CNMR (75 MHz, CDCl₃) δ 153.1, 143.8, 140.0, 139.3, 129.1, 129.1, 127.1,126.9, 126.1, 125.4, 106.2, 59.1, 15.4. Mass spectrum (API-TIS) m/z 297(MH⁺), 279 (M-OH). Anal. calcd. for C₁₇H₁₆N₂O₁S: C, 68.89; H, 5.44; N,9.45. Found: C, 68.80; H, 5.34; N, 9.34.

11c.1-((3Z)-4-(5-(4-methylthiophenyl)-1-phenylpyrazol-3-yl)but-3-enyloxy)-1,1,2,2-tetramethyl-1-silapropaneand 1-((3E)-4-(5-(4-methylthiophenyl)-1-phenylpyrazol-3-yl)but-3-enyloxy)-1,1,2,2-tetramethyl-1-silapropane

Activated MnO₂ (4.49 g, 51.6 mmol) was dried under high vacuum for 2days at 70° C. Dried MnO₂ (2 g, 23.0 mmol) was then added to a solutionof the product of Example 11a (3.08 g, 10.4 mmol),(3-((1,1-dimethylethyl)-dimethylsilyl)oxy)propyl)-triphenylphosphoniumbromide (5.9 g, 11.5 mmol),1,3,4,6,7,8-hexahydro-1-methyl-2H-pyrimido(1,2-a)pyrimidine (3.45 g,22.5 mmol), Ti(i-OPr)₄ (2.95 g, 10.4 mmol) in dry THF (250 mL) which washeated to reflux under nitrogen. A second portion of MnO₂ (2.49 g, 28.6mmol) was added after 1 h and the reaction mixture was heated for 4 h.The reaction mixture was allowed to cool to room temperature and thenfiltered through the Celite pad and washed with EtOAc. The residueobtained after evaporation of the solvent, was purified bychromatography over silica gel eluting with 1:2 EtOAc:Hexane to give thetitle compounds as a colorless oil. Z-isomer: (1.84 g, 39% yield), andE-isomer (0.3 g, 6% yield). Z-isomer: ¹H NMR (300 MHz, CDCl₃) δ7.25-7.40 (m, 5H), 7.10-7.20 (m, 4H), 6.57 (s, 1H), 6.52 (d, J=11.7 Hz,1H), 5.78-5.88 (m, 1H), 3.79 (t, J=6.8 Hz, 2H), 2.77 (q, J=1.3 Hz, 2H),2.48 (s, 3H), 0.91 (s, 9H), 0.08 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ150.2, 143.1, 140.2, 139.2, 130.5, 129.2, 129.1, 127.5, 127.2, 126.1,125.3, 122.1, 108.0, 62.8, 33.1, 26.1, 18.5, 15.5, −5.0. Mass spectrum(API-TIS) m/z 451 (MH⁺).

11d.1-(3-((1Z)-4-(Hydroxy)but-1-enyl)-1-phenylpyrazol-5-yl)-4-methylsulfonyl)benzene

The title compound was prepared as a white solid from the product ofExample 11c by following the procedure for Example 3e. Mp 104-105° C. ¹HNMR (300 MHz, CDCl₃) δ 7.87 (dd, J=1.8 and 8.5 Hz, 2H), 7.42 (dd, J=1.8and 8.4 Hz, 2H), 7.32-7.38 (m, 3H), 7.22-7.29 (m, 2H), 6.60 (s, 1H),6.55 (d, J=11.6 Hz, 1H), 5.87-5.98 (m, 1H), 3.84 (q, J=5.9 Hz, 2H), 3.06(s, 3H), 2.93 (t, J=5.0 Hz, 1H), 2.83 (q, J=5.0 Hz, 2H). ¹³C NMR (75MHz, CDCl₃) δ 150.0, 141.6, 140.2, 139.4, 135.8, 131.4, 129.5, 129.5,128.3, 127.8, 125.3, 122.6, 109.4, 62.5, 44.6, 32.6. Mass spectrum(API-TIS) m/z 369 (MH⁺). Anal. calcd. for C₂₀H₂₀N₂O₃S: C, 65.20; H,5.47; N, 7.60. Found: C, 65.01; H, 5.21; N, 7.53.

11e.1-(3-((1Z)-4-(Nitrooxy)but-1-enyl)-1-phenylpyrazol-5-yl)-4-(methylsulfonyl)benzene

Fuming HNO₃ (2.2 mL, 3.28 g, 52.1 mmol) was added drop-wise to asolution of the product of Example 11d (0.64 g, 1.7 mmol) in CHCl₃ at 0°C. and then stirred at room temperature for 30 min. The solution wasextracted with CH₂Cl₂, washed with saturated NaHCO₃, water, dried overNa₂SO₄, and filtered. The residue after evaporation of the solventpurified by chromatography over silica gel eluting with 1:2 EtOAc:Hexaneto give the product as a pale yellow foam (0.72 g, 100% yield). ¹H NMR(300 MHz, CDCl₃) δ 7.88 (d, J=8.2 Hz, 2H), 7.43 (d, J=8.2 Hz, 2H),7.23-7.40 (m, 5H), 6.60 (s, 1H), 6.54 (d, J=11.5 Hz, 1H), 5.73-5.87 (m,1H), 4.64 (t, J=6.7 Hz, 2H), 3.07 (s, 3H), 2.61-2.65 (m, 2H); ¹³C NMR(75 MHz, CDCl₃) δ 149.6, 141.5, 140.2, 139.5, 135.8, 129.4, 129.4,128.2, 127.7, 127.4, 125.2, 123.3, 109.5, 72.5, 44.5, 27.3. Massspectrum (API-TIS) m/z 414 (MH⁺). Anal. calcd. for C₂₀H₁₉N₃O₅S.0.85 molH₂O: C, 56.02; H, 4.86; N, 9.80. Found: C, 56.28; H, 4.85; N, 9.41.

11f.1-(3-((1E)-4-(Nitrooxy)but-1-enyl)-1-phenylpyrazol-5-yl)-4-(methylsulfonyl)benzene

Prepared as in Example 11e to give the title compound as a white foam.¹H NMR (300 MHz, CDCl₃) δ 7.86 (d, J=8.3 Hz, 2H), 7.41 (d, J=8.3 Hz,2H), 7.20-7.48 (m, 5H), 6.68 (s, 1H), 6.61 (d, J=16.0 Hz, 1H), 6.25-6.40(m, 1H), 4.58 (t, J=6.6 Hz, 2H), 3.06 (s, 3H), 2.68 (q, J=6.6 Hz, 2H);¹³C NMR (75 MHz, CDCl₃) δ 150.8, 142.0, 140.1, 139.5, 135.7, 129.4,129.3, 128.2, 127.7, 126.7, 125.3, 125.1, 105.9, 72.1, 44.4, 30.5. Massspectrum (API-TIS) m/z 414 (MH⁺). Anal. Calcd. for C₂₀H₁₉N₃O₅S: C,58.10; H, 4.63; N, 10.16. Found: C, 58.36; H, 4.75; N, 9.88.

Example 121-(1-(4-Methylphenyl)-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-4-(nitrooxy)butan-1-one12a. Methyl1-(4-methylphenyl)-5-(4-methylthiophenyl)pyrazol-3-carboxylate

The title compound was prepared as a white solid (4.258 g, 63% yield)from the product of Example 1d (5.05 g, 20 mmol) and4-methylphenylhydrazine hydrochloride (4.12 g, 26 mmol) following theprocedure of Example 8a. Mp 113-115° C. ¹H NMR (300 MHz, CDCl₃) δ7.29-7.13 (m, 8H), 7.04 (s, 1H), 3.99 (s, 3H), 2.50 (s, 3H), 2.40 (s,3H). Mass spectrum (API-TIS) m/z 339 (MH⁺). Anal. calcd. forC₁₉H₁₈N₂O₂S: C, 67.43; H, 5.36; N, 8.28. Found: C, 67.62; H, 5.27; N,8.20.

12b.N-Methoxy-N-methyl(1-(4-methylphenyl)-5-(4-methylthiophenyl)pyrazol-3-yl)carboxamide

The title compound was prepared as a white solid from the product ofExample 12a by following the procedure for Example 3c. ¹H NMR (300 MHz,CDCl₃) δ 7.14-7.30 (m, 8H), 6.98 (s, 1H), 3.87 (s, 3H), 3.53 (br s, 3H),2.49 (s, 3H), 2.39 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 145.8, 143.3,139.6, 138.1, 137.4, 129.7, 129.1, 126.4, 126.0, 125.3, 109.9, 61.7,35.0, 21.2, 15.4. Mass spectrum (API-TIS) m/z 368 (MH⁺). Anal. calcd.for C₂₀H₂₁N₃O₂S: C, 65.37; H, 5.76; N, 11.43. Found: C, 65.03; H, 5.54;N, 11.17.

12c.1-(1-(4-Methylphenyl)-5-(4-methylthiophenyl)pyrazol-3-yl)-4-(1,1,2,2-tetramethyl-1-silapropoxy)butan-1-one

The title compound was prepared as a white solid from the product ofExample 12b by following the procedure for Example 3d. ¹H NMR (300 MHz,CDCl₃) δ 7.13-7.26 (m, 8H), 6.96 (s, 1H), 3.71 (t, J=6.4 Hz, 2H), 3.15(t, J=7.3 Hz, 2H), 2.48 (s, 3H), 2.38 (s, 3H), 1.92-2.05 (m, 2H), 0.86(s, 9H), 0.05 (s, 6H). ¹³C NMR (75 MHz, CDCl₃) δ 196.6, 151.4, 144.3,139.8, 138.4, 137.4, 129.8, 129.1, 126.3, 126.0, 125.3, 107.4, 62.7,35.2, 27.5, 26.1, 21.2, 18.4, 15.3, −5.2. Mass spectrum (API-TIS) m/z481 (MH⁺). Anal. calcd. for C₂₇H₃₆N₂O₂SSi: C, 67.46; H, 7.55; N, 5.83.Found: C, 67.40; H, 7.76; N, 5.74.

12d.4-Hydroxy-1-(1-(4-methylphenyl)-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)butan-1-one

The product of Example 12c (1.64 g, 3.42 mmol) was dissolved in MeOH (60mL). OXONE® (6.30 g, 10.25 mmol) in water (20 mL) was added at roomtemperature. The reaction mixture was stirred for 1 hour and theresulting solid was removed by filtration. The filtrate was diluted withCH₂Cl₂, washed with saturated NaHCO₃ and water, dried over Na₂SO₄. andfiltered. The residue, after evaporation of the solvent, was purified bychromatography over silica gel eluting with 1:2 to 1:1 to 2:1EtOAc:Hexane to give the title compound (0.8 g, 59% yield) as a whitesolid. Mp 159-161° C. ¹H NMR (300 MHz, CDCl₃) δ 7.88 (dd, J=1.7 and 6.8Hz, 2H), 7.41 (dd, J=1.7 and 6.8 Hz, 2H), 7.16-7.23 (m, 4H), 7.10 (s,1H), 3.73 (q, J=6.0 Hz, 2H), 3.23 (t, J=6.95 Hz, 2H), 3.07 (s, 3H), 2.41(s, 3H), 2.10 (bt, J=5.70 Hz, 1H), 2.06 (p, J=6.5 Hz, 2H); ¹³C NMR (75MHz, CDCl₃) δ 196.4, 152.0, 143.0, 141.0, 138.1, 134.7, 132.8, 129.6,128.1, 127.0, 123.0, 109.2, 62.4, 44.5, 35.6, 27.3. Mass spectrum(API-TIS) m/z 399 (MH⁺), 381 (M-OH). Anal. calcd. for C₂₁H₂₂N₂O₄S.½H₂O:C, 61.90; H, 5.68; N, 6.87. Found: C, 62.29; H, 5.41; N, 6.82.

12e.1-(1-(4-Methylphenyl)-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-4-(nitrooxy)butan-1-one

The title compound was prepared as a white solid from the product ofExample 12d by following the procedure for Example 1h. Mp 107-109° C. ¹HNMR (300 MHz, CDCl₃) δ 7.89 (dd, J=1.7 and 6.8 Hz, 2H), 7.42 (dd, J=2.9and 8.5 Hz, 2H), 7.16-7.24 (m, 4H), 7.10 (s, 1H), 4.58 (t, J=6.4 Hz,2H), 3.26 (t, J=7.1 Hz, 2H), 3.07 (s, 3H), 2.42 (s, 3H), 2.22 (p, J=6.8Hz, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 194.3, 151.2, 143.1, 140.7, 139.4,136.7, 135.1, 130.2, 129.6, 127.9, 125.4, 108.6, 72.7, 44.5, 34.6, 21.3.Mass spectrum (API-TIS) m/z 444 (MH⁺). Anal. calcd. for C₂₁H₂₁N₃O₆S: C,56.88; H, 4.77; N, 9.48. Found: C, 56.87; H, 4.69; N, 9.39.

Example 131-(1-(4-Fluorophenyl)-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-4-(nitrooxy)butan-1-one13a. Methyl1-(4-fluorophenyl)-5-(4-methylthiophenyl)pyrazol-3-carboxylate

The title compound was prepared from the product of Example 1d (5.05 g,20 mmol) and 4-fluorophenylhydrazine hydrochloride (4.23 g, 26 mmol) inmethanol (120 mL) using the procedure of Example 10a. Separation of theregioisomers and recrystallization gave the title compound (5.124 g, 75%yield) as a white solid. Mp 117-119° C. ¹H NMR (300 MHz, CDCl₃) δ7.37-7.31 (m, 2H), 7.22-7.05 (m, 7H), 4.00 (s, 3H), 2.51 (s, 3H). Massspectrum (API-TIS) m/z 343 (MH⁺). Anal. calcd. for C₁₈H₁₅FN₂O₂S: C,63.14; H, 4.42; N, 8.18. Found: C, 63.08; H, 4.41; N, 8.19.

13b.(1-(4-Fluorophenyl)-5-(4-methylthiophenyl)pyrazol-3-yl)-N-methoxy-N-methylcarboxamide

The title compound was prepared as a white solid from the product ofExample 13a using the procedure of Example 3c. Mp 91-93° C. ¹H NMR (300MHz, CDCl₃) δ 7.02-7.33 (m, 8H), 6.96 (s, 1H), 3.84 (s, 3H), 3.50 (br s,3H), 2.48 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 162.1 (J=248.5 Hz), 146.1,143.5, 140.1, 136.0, 129.2, 127.4, 127.3, 126.1 (J=5.2 Hz), 116.1(J=23.1 Hz), 110.1, 61.8, 34.0, 15.4. Mass spectrum (API-TIS) m/z 372(MH⁺), 394 (MNa⁺). Anal. calcd. for C₁₉H₁₈FN₃O₂S: C, 61.44; H, 4.88; N,11.31. Found: C, 61.35; H, 4.86; N, 11.25.

13c.1-(1-(4-Fluorophenyl)-5-(4-methylthiophenyl)pyrazol-3-yl)-4-(1,1,2,2-tetramethyl-1-silapropoxy)butan-1-one

The title compound was prepared as a white solid from the product ofExample 13b using the procedure of Example 3d. Mp 46-47° C. ¹H NMR (300MHz, CDCl₃) δ 7.02-7.42 (m, 8H), 6.96 (s, 1H), 3.72 (t, J=6.4 Hz, 2H),3.15 (t, J=7.3 Hz, 2H), 2.48 (s, 3H), 1.99 (p, J=7.0 Hz, 2H), 0.88 (s,9H), 0.05 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 196.5, 162.2 (J_(C-F)=248.8Hz), 151.6, 144.6, 140.2, 136.0, 135.9, 129.1, 127.4, 127.3, 126.0(J_(C-F)=11.4 Hz), 116.2 (J_(C-F)=116.2 Hz), 107.8, 62.7, 35.3, 27.5,26.1, 18.5, 15.3, −5.1. Mass spectrum (API-TIS) m/z 485 (MH⁺). Anal.calcd. for C₂₆H₃₃FN₂O₂SSi: C, 64.43; H, 6.86; N, 5.78. Found: C, 64.29;H, 6.72; N, 5.70.

13d.1-(1-(4-Fluorophenyl)-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-4-hydroxybutan-1-one

The title compound was prepared as a white solid from the product ofExample 13c using the procedure of Example 12d. Mp 164-166° C. ¹H NMR(300 MHz, CDCl₃) δ 7.91 (d, J=8.5 Hz, 2H), 7.40 (d, J=6.6 Hz, 2H),7.27-7.34 (m, 2H), 7.08-7.17 (m, 2H), 7.11 (s, 1H), 3.74 (q, J=6.0 Hz,2H), 3.23 (t, J=7.0 Hz, 2H), 3.08 (s, 3H), 1.97-2.07 (m, 3H); ¹³C NMR(75 MHz, CDCl₃) δ196.4, 162.5 (J_(C-F)=250.4 Hz), 151.7, 143.1, 140.9,135.3, 134.7, 129.6, 128.0, 127.5 (J_(C-F)=8.8 Hz), 116.7 (J_(C-F)=23.2Hz), 108.9, 62.3, 44.4, 35.5, 27.3. Mass spectrum (API-TIS) m/z 403(MH⁺), 385 (M-OH). Anal. Calcd. for C₂₀H₁₉FN₂O₄S: C, 59.69; H, 4.76; N,6.96. Found: C, 59.40; H, 4.84; N, 6.71.

13e.1-(1-(4-Fluorophenyl)-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-4-(nitrooxy)butan-1-one

The title compound was prepared as a white solid from the product ofExample 13d using the procedure of Example 1h. Mp 134-136° C. ¹H NMR(300 MHz, CDCl₃) δ 7.91 (d, J=6.8 Hz, 2H), 7.41 (d, J=6.7 Hz, 2H),7.25-7.37 (m, 2H), 7.13-7.16 (m, 2H), 7.11 (s, 1H), 4.59 (t, J=6.4 Hz,2H), 3.26 (t, J=7.1 Hz, 2H), 3.08 (s, 3H), 2.22 (p, J=6.8 Hz, 2H); ¹³CNMR (75 MHz, CDCl₃) δ 194.4, 162.6 (J_(C-F)=250.3 Hz), 151.4, 143.3,141.0, 135.3, 134.7, 129.6, 128.1, 127.5 (J_(C-F)=8.8 Hz), 116.8(J_(C-F)=23.2 Hz), 108.9, 72.6, 44.5, 34.7, 21.3. Mass spectrum(API-TIS) m/z 448 (MH⁺), 465 (MNH₄ ⁺), 470 (MNa⁺). Anal. calcd. forC₂₀H₁₈FN₃O₆S: C, 53.69; H, 4.05; N, 9.39. Found: C, 53.47; H, 4.05; N,9.26.

Example 141-(1-(4-Bromophenyl)-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-4-(nitrooxy)butan-1-one14a. Methyl1-(4-bromophenyl)-5-(4-methylthiophenyl)pyrazol-3-carboxylate

The title compound was prepared from the product of Example 1d (5.05 g,20 mmol) and 4-bromophenylhydrazine hydrochloride (5.81 g, 26 mmol) inmethanol (120 mL) using the procedure for Example 8a. Separation of theregioisomers and recrystallization provided the title compound (6.798 g,84% yield) as a white solid. Mp 138-140° C. ¹H NMR (300 MHz, CDCl₃) δ7.49 (d, J=8.6 Hz, 2H), 7.25 (d, J=8.9 Hz, 2H), 7.19 (d, J=8.9 Hz, 2H),7.11 (d, J=8.6 Hz, 2H), 7.01 (s, 1H), 3.97 (s, 3H), 2.49 (s, 3H). Massspectrum (API-TIS) m/z 405 (MH⁺). Anal. calcd. for C₁₈H₁₅BrN₂O₂S: C,53.61; H, 3.75; N, 6.95. found: C, 53.67; H, 3.60; N, 6.89.

14b.(1-(4-Bromophenyl)-5-(4-methylthiophenyl)pyrazol-3-yl)-N-methoxy-N-methylcarboxamide

The title compound was prepared as a white solid from the product ofExample 14a using the procedure of Example 3c. Mp 151-153° C. ¹H NMR(300 MHz, CDCl₃) δ 7.47 (d, J=6.8 Hz, 2H), 7.15-7.25 (m, 6H), 6.95 (s,1H), 3.84 (s, 3H), 3.49 (br s, 3H), 2.48 (s, 3H); ¹³C NMR (75 MHz,CDCl₃) δ 141.0, 138.1, 134.9, 133.5, 126.9, 123.8, 121.5, 120.8, 120.6,116.5, 105.1, 56.4, 29.0, 10.0. Mass spectrum (API-TIS) m/z 432/434(MH⁺). Anal. calcd. for C₁₉H₁₈BrN₃O₂S: C, 52.79; H, 4.20; N, 9.72.Found: C, 52.67; H, 4.15; N, 9.70.

14c.1-(1-(4-Bromophenyl)-5-(4-methylthiophenyl)pyrazol-3-yl)-4-(1,1,2,2-tetramethyl-1-silapropoxy)butan-1-one

The title compound was prepared as a colorless oil from the product ofExample 14b using the procedure of Example 3d. ¹H NMR (300 MHz, CDCl₃) δ7.50 (d, J=6.9 Hz, 2H), 7.08-7.27 (m, 6H), 6.96 (s, 1H), 3.72 (t, J=6.4Hz, 2H), 3.14 (t, J=7.31 Hz, 2H), 2.49 (s, 3H), 1.99 (p, J=6.9 Hz, 2H),0.86 (s, 9H), 0.05 (s, 6H). ¹³C NMR (75 MHz, CDCl₃) δ 196.5, 151.8,144.5, 140.4, 138.8, 132.4, 129.2, 126.9, 126.2, 125.9, 122.2, 108.0,62.7, 35.4, 27.5, 26.1, 18.5, 15.3, −5.1. Mass spectrum (API-TIS) m/z545/547 (MH⁺). Anal. calcd. for C₂₆H₃₃BrN₂O₂SSi: C, 57.24; H, 6.10; N,5.13. Found: C, 56.95; H, 6.02; N, 4.97.

14d.1-(1-(4-Bromophenyl)-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-4-hydroxybutan-1-one

The title compound was prepared as a white solid from the product ofExample 14c using the procedure of Example 12d. Mp 136-137° C. ¹H NMR(300 MHz, CDCl₃) δ 7.93 (d, J=8.3 Hz, 2H), 7.56 (d, J=8.6 Hz, 2H), 7.42(d, J=8.3 Hz, 2H), 7.19 (dd, J=1.7 and 8.6 Hz, 2H), 7.10 (s, 1H), 3.74(m, 2H), 3.23 (t, J=6.97 Hz, 2H), 3.09 (s, 3H), 2.04 (p, J=6.6 Hz, 2H),1.93 (t, J=5.6 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 196.4, 152.0, 143.0,141.0, 138.1, 134.7, 132.8, 129.6, 128.1, 127.0, 123.0, 109.2, 62.4,44.5, 35.6, 27.3. Mass spectrum (API-TIS) m/z 463/465 (MH⁺). Anal.calcd. for C₂₀H₁₉BrN₂O₄S: C, 51.84; H, 4.13; N, 6.05. Found: C, 51.57;H, 4.07; N, 5.79.

14e.1-(1-(4-Bromophenyl)-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-4-(nitrooxy)butan-1-one

The title compound was prepared as a white solid from the product ofExample 14d using the procedure of Example 1h. Mp 150-152° C. ¹H NMR(300 MHz, CDCl₃) δ 7.96 (dd, J=1.7 and 6.8 Hz, 2H), 7.59 (dd, J=1.9 and6.9 Hz, 2H), 7.45 (dd J=1.7 and 8.5 Hz, 2H), 7.23 (dd, J=2.8 and 8.8 Hz,2H), 7.13 (s, 1H), 4.61 (t, J=6.4 Hz, 2H), 3.28 (t, J=7.08 Hz, 2H), 3.12(s, 3H), 2.24 (p, J=6.6 Hz, 2H). ¹³C NMR (75 MHz, CDCl₃) δ 194.3, 151.6,143.1, 141.1, 138.1, 134.7, 132.8, 129.6, 128.1, 127.0, 123.1, 109.1,72.6, 44.5, 34.7, 21.3. Mass spectrum (API-TIS) m/z 508/510 (MH⁺). Anal.Calcd. for C₂₀H₁₈BrN₃O₆S: C, 47.26; H, 3.57; N, 8.27. Found: C, 47.55;H, 3.47; N, 7.96.

Example 151-(1-Cyclohexyl-3-((2-(nitrooxy)ethoxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene15a.4-(1-Cyclohexyl-3-(hydroxymethyl)pyrazol-5-yl)-1-(methylsulfonyl)benzene

The product of Example 4b (0.6 g, 2.0 mmol) was dissolved in a mixtureof MeOH (20 mL) and water (8 mL) and cooled to 0° C. OXONE® (3 g) wasadded and the resulting suspension was stirred at 0° C. for 1 hour.Water (25 mL) and 15% NH₄OH (25 mL) were added. The mixture wasextracted with EtOAC (3×25 mL) and the organic extracts were dried overNa₂SO₄. The solvent was evaporated under reduced pressure to give whitesolid which was recrystallized from CH₂Cl₂ (5 mL) and hexane (20 mL) togive the title compound (0.62 g, 94% yield) as a white solid. Mp 148° C.¹H NMR (300 MHz, CDCl₃) δ 8.03 (d, J=8.3 Hz, 2H), 7.56 (d, J=8.3 Hz,2H), 6.31 (s, 1H), 4.73 (s, 2H), 3.90-4.10 (m, 1H), 3.13 (s, 3H), 2.45(s, 1H, OH), 1.66-2.05 (m, 7H), 1.10-1.25 (m, 3H); ¹³C NMR (75 MHz,CDCl₃) δ 151.4, 141.7, 140.4, 136.5, 129.7, 127.9, 105.0, 59.0, 58.2,44.4, 33.3, 25.6, 25.0. Mass spectrum (API-TIS), m/z 335 (MH⁺).

15b.1-(3-(Bromomethyl)-1-cyclohexylpyrazol-5-yl)-4-(methylsulfonyl)benzene

The product of Example 15a (2.0 g, 5.9 mmol) and PBr₃ (1.1 mL, 11.7mmol) were taken up in CH₂Cl₂ (10 mL) and stirred at room temperatureovernight. Aqueous work-up followed by drying over MgSO₄ and evaporationof the solvent under reduced pressure gave the title compound (1.9 g,83% yield) as a yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 8.04 (d, J=8.4Hz, 2H), 7.56 (d, J=8.4 Hz, 2H), 6.36 (s, 1H), 4.53 (s, 2H), 3.99-3.44(m, 1H), 3.12 (s, 3H), 2.03-1.87 (m, 5H), 1.67 (m, 2H), 1.28-1.26 (m,3H). Mass spectrum (API-TIS) m/z 398 (MH⁺).

15c.1-(1-Cyclohexyl-3-((2-(phenylmethoxy)ethoxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene

2-Benzyloxy-1-ethanol (1.5 g, 10.1 mmol) was added to a stirred solutionof NaH (240.8 mg, 10.1 mmol) in dry THF (10 mL) and the reaction mixturestirred for 15 minutes. The product of Example 15b (2.0 g, 5.0 mmol) wasadded and the mixture stirred overnight. The sample was diluted withCH₂Cl₂ (10 mL) and washed with saturated NH₄Cl and brine. The sample wasdried over Mg₂SO₄ and the solvent evaporated under reduced pressure. Theresulting residue was purified by chromatography over silica gel elutingwith 3:1 Hexanes/EtOAc to give the title compound (1.3 g, 51% yield) asa yellow oil. ¹H NMR (300 MHz, CDCl₃) δ 8.02 (d, J=8.3 Hz, 2H), 7.54 (d,J=8.3 Hz, 2H), 7.36-7.27 (m, 5H), 6.35 (s, 1H), 4.61 (s, 2H), 4.57 (s,2H), 3.99-3.94 (m, 1H), 3.75-3.72 (m, 2H), 3.68-3.65 (m, 2H), 3.12 (s,3H), 2.04-1.98 (m, 3H), 1.88-1.83 (m, 4H), 1.65-1.60 (m, 3H). Massspectrum (API-TIS) m/z 469 (MH⁺).

15d.1-(1-Cyclohexyl-3-((2-hydroxyethoxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene

The product of Example 15c (1.3 g, 2.8 mmol) was dissolved in EtOH (100mL) and placed in a Parr shaker. Pd/C (500 mg) was added and the sampleflushed with nitrogen 4 times. The sample was then flushed several timeswith H₂ (25-30 psi). The hydrogenation was performed at 30 psi in a H₂atmosphere for 30 minutes. The catalyst was removed via filtrationthrough Celite and washed with additional EtOH. The combined filtratewas evaporated under reduced pressure, to give the title compound (513.7mg, 49% yield) as a yellow oil. ¹H NMR (300 MHz, CDCl₃) δ 8.04 (d, J=8.4Hz, 2H), 7.56 (d, J=8.4 Hz, 2H), 6.30 (s, 1H), 4.62 (s, 2H), 4.03-3.94(m, 1H), 3.78-3.76 (m, 2H), 3.69-3.67 (m, 2H), 3.13 (s, 3H), 2.66 (br s,1H), 2.06-1.99 (m, 2H), 1.90-1.86 (m, 2H), 1.66-1.62 (m, 3H), 1.28-1.22(m, 3H). Mass spectrum (API-TIS) m/z 379 (MH⁺).

15e.1-(1-Cyclohexyl-3-((2-(nitrooxy)ethoxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene

Fuming nitric acid (5 mL) was cooled to 0° C. and the product of Example15d (175.0 mg, 0.46 mmol) was added drop-wise. The reaction mixture wasstirred at 0° C. for 1 hour. Water (5 mL) was added followed by Na₂CO₃until the mixture was neutralized. CH₂Cl₂ was added and the organicsseparated. The aqueous portion was extracted with additional CH₂Cl₂ andthe combined organic fractions were washed with water, dried over MgSO₄and the solvent was evaporated under reduced pressure to give the titlecompound (93.5 mg, 48% yield) as a pale yellow solid. ¹H NMR (300 MHz,CDCl₃) δ 8.04 (d, J=8.4 Hz, 2H), 7.57 (d, J=8.4 Hz, 2H), 6.33 (s, 1H),4.65-4.61 (m, 2H), 4.60 (s, 2H), 3.99-3.93 (m, 1H), 3.84-3.81 (m, 2H),3.13 (s, 3H), 2.04-1.98 (m, 2H), 1.89-1.86 (m, 3H), 1.58-1.53 (m, 2H),1.28-1.22 (m, 3H). Mass spectrum (API-TIS) m/z 424 (MH⁺).

Example 161-(1-Cyclohexyl-3-((3-(nitrooxy)propoxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene16a.1-(1-Cyclohexyl-3-((3-phenoxypropoxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene

3-Benzyloxy-1-propanol (1.5 g, 9.6 mmol) was added to a stirred solutionof NaH (228.7 mg, 9.6 mmol) in dry THF (10 mL) and the reaction mixturestirred for 15 minutes at room temperature. The product of Example 15b(1.9 g, 4.8 mmol) was added and the mixture stirred overnight. Thesample was diluted with CH₂Cl₂ (10 mL) and washed with saturated NH₄Cl,brine, dried over Mg₂SO₄ and the solvent was evaporated under reducedpressure. The resulting residue was purified by chromatography oversilica gel eluting with 3:1 Hexanes/EtOAc to give the title compound(1.2 g, 50% yield) as a yellow oil. ¹H NMR (300 MHz, CDCl₃) δ 8.02 (d,J=8.4 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.32-7.26 (m, 5H), 6.31 (s, 1H),4.54 (s, 2H), 4.50 (s, 2H), 3.99-3.94 (m, 1H), 3.66 (t, J=6.4 Hz, 2H),3.59 (t, J=6.4 Hz, 2H), 3.12 (s, 3H), 2.07-2.04 (m, 2H), 1.94 (q, J=6.4Hz, 2H), 1.65-1.61 (m, 3H), 1.28-1.22 (m, 3H). Mass spectrum (API-TIS)m/z 483 (MH⁺)

16b.1-(1-Cyclohexyl-3-((3-hydroxypropoxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene

The product of Example 16a (1.3 g, 2.3 mmol) was dissolved in EtOH (100mL) and placed in a Parr shaker. Pd/C (500 mg) was added and the sampleflushed with nitrogen 4 times. The sample was then flushed several timeswith H₂ (25-30 psi). The flask was refilled to 30 psi with H₂ and thesample shaken for 30 minutes. The solid was removed via filtrationthrough Celite and washed with additional EtOH. The filtrate wascollected, dried over MgSO₄ and the solvent was evaporated under reducedpressure to give the title compound (727.9 mg, 80% yield) as a yellowoil. ¹H NMR (300 MHz, CDCl₃) δ 8.04 (d, J=8.5 Hz, 2H), 7.55 (d, J=8.5Hz, 2H), 6.29 (s, 1H), 4.57 (s, 2H), 4.03-3.94 (m, 2H), 3.79-3.76 (m,1H), 3.75 (t, J=5.8 Hz, 2H), 3.12 (s, 3H), 2.58 (br s, 1H), 2.07-2.03(m, 2H), 1.99-1.83 (m, 3H), 1.87 (q, J=5.8 Hz, 2H), 1.65-1.59 (m, 2H),1.28-1.21 (m, 3H). Mass spectrum (API-TIS) m/z 393 (MH⁺).

16c.1-(1-Cyclohexyl-3-((3-(nitrooxy)propoxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene

Fuming nitric acid (5 ml) was cooled to 0° C. and the product of Example16b (105.5 mg, 0.27 mmol) in EtoAc was added drop-wise. The reactionmixture was stirred at 0° C. for 1 hour. Water (5 mL) was added followedby Na₂CO₃ until the mixture was neutralized. CH₂Cl₂ was added and theorganics separated. The aqueous portion was extracted with additionalCH₂Cl₂ and the combined organic fractions were washed with water, driedover MgSO₄ and the solvent was evaporated under reduced pressure to givethe title compound (49.1 mg, 41% yield) as a pale yellow solid. ¹H NMR(300 MHz, CDCl₃) δ 8.03 (d, J=8.3 Hz, 2H), 7.30 (d, J=8.3 Hz, 2H), 6.30(s, 1H), 4.56 (t, J=6.0 Hz, 2H), 4.53 (s, 2H), 4.02-3.94 (m, 1H), 3.62(t, J=6.0 Hz, 2H), 3.11 (s, 3H), 2.04-1.97 (m, 3H), 2.01 (q, J=6.0 Hz,2H), 1.88-1.86 (m, 3H), 1.65 (br s, 1H), 1.27-1.21 (m, 3H). Massspectrum (API-TIS) m/z 438 (MH⁺).

Example 171-(1-Cyclohexyl-3-((3-((nitrooxy)methyl)phenoxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene17a. Ethyl3-((1-cyclohexyl-5-(4-(methylsulfonyl)phenyl)pyrazol-3-)methoxy)benzoate

The product of Example 15b (562.2 mg, 1.4 mmol), ethyl-3-hydroxybenzoate(259.5 mg, 1.6 mmol), K₂CO₃ (294.2 mg, 2.1 mmol), and NaI (233.8 mg, 1.6mmol) were taken up in acetone (10 mL) and stirred at reflux overnight.Aqueous work-up followed by drying over MgSO₄ and removal of the solventunder reduced pressure gave the title compound (377.1 mg, 55% yield) asa white foam. ¹H NMR (300 MHz, CDCl₃) δ 8.03 (d, J=8.3 Hz, 2H), 7.69 (brs, 1H), 7.63 (d, J=7.6 Hz, 1H), 7.56 (d, J=8.3 Hz, 2H), 7.33 (t, J=8.3Hz, 1H), 7.19 (dd, J=2.1 Hz, 8.3, 1H), 6.40 (s, 1H), 5.14 (s, 2H), 4.35(q, J=7.1 Hz, 2H), 4.05-3.98 (m, 1H), 3.11 (s, 3H), 2.06-2.00 (m, 2H),1.91-1.84 (m, 4H), 1.65 (br s, 1H), 1.37 (t, J=7.1 Hz, 3H), 1.31-1.26(m, 3H). Mass spectrum (API-TIS) m/z 483 (MH⁺).

17b.1-(1-Cyclohexyl-3-((3-(hydroxymethyl)phenoxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene

The product of Example 17a (377.1 mg, 0.78 mmol) was dissolved in dryTHF (7 mL) and cooled to 0° C. A 1M lithium aluminum hydride solution(1.02 mL, 1.02 mmol) was added drop-wise and the mixture stirred at 0°C. for 3.5 hours. Solid Na₂SO₄.10H₂O was added until a solid formed. Theprecipitate was removed via filtration and washed with 10% MeOH/CH₂Cl₂.The filtrate was collected, dried over Mg₂SO₄, and the solvent wasevaporated under reduced pressure. The resulting residue was purified bychromatography over silica gel eluting with 2.5% MeOH/CHCl₃ to give thetitle compound (214.1 mg, 62% yield) as a clear oil. ¹H NMR (300 MHz,CDCl₃) δ 8.00 (d, J=8.3 Hz, 2H), 7.54 (d, J=8.3 Hz, 2H), 7.22 (d, J=7.9Hz, 2H), 7.01 (br s, 1H), 6.93-6.86 (m, 2H), 6.38 (s, 1H), 5.10 (s, 2H),4.62 (d, J=4.6 Hz, 2H), 4.04-3.97 (m, 1H), 3.08 (s, 3H), 2.04-1.97 (m,2H), 1.89-1.80 (m, 4H), 1.64 (br s, 1H), 1.29-1.24 (m, 3H). Massspectrum (API-TIS) m/z 441 (MH⁺).

17c.1-(3-((3-(Bromomethyl)phenoxy)methyl)-1-cyclohexylpyrazol-5-yl)-4-(methylsulfonyl)benzene

The product of Example 17b (204.8 mg, 0.46 mmol) and PBr₃ (88.4 μL, 0.93mmol) were taken up in CH₂Cl₂ (3 mL) and stirred overnight. Aqueouswork-up followed by drying over MgSO₄ and removal of the solvent underreduced pressure afforded the title compound (161.6 mg, 69% yield) as aclear oil. ¹H NMR (300 MHz, CDCl₃) δ 8.02 (d, J=8.2 Hz, 2H), 7.55 (d,J=8.2 Hz, 2H), 7.22 (t, J=7.9 Hz, 2H), 6.96-6.92 (m, 2H), 6.40 (s, 1H),5.10 (s, 2H), 4.43 (s, 2H), 4.06-3.98 (m, 1H), 3.09 (s, 3H), 2.06-2.03(m, 3H), 1.91-1.87 (m, 3H), 1.65 (br s, 1H), 1.29-1.22 (m, 3H). Massspectrum (API-TIS) m/z 504 (MH⁺).

17d.1-(1-Cyclohexyl-3-((3-((nitrooxy)methyl)phenoxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene

The product of Example 17c (161.6 mg, 0.32 mmol) was dissolved inacetonitrile (5 mL) and AgNO₃ (109.3 mg, 0.64 mmol) was added. Themixture was shielded from light and stirred at room temperatureovernight. 1N HCl (4 mL) was added and the precipitate removed viafiltration through Celite. The aqueous layer was separated and extractedwith methylene chloride. The combined extracts were washed with water,dried over MgSO₄ and the solvent evaporated under reduced pressure togive the title compound (67.0 mg, 43% yield) as a yellow oil. ¹H NMR(300 MHz, CDCl₃); δ8.04 (d, J=8.2 Hz, 2H), 7.57 (d, J=8.2 Hz, 2H), 7.31(t, J=7.6 Hz, 1H), 7.06-7.03 (m, 2H), 6.98 (d, J=7.6 Hz, 1H), 6.40 (s,1H), 5.39 (s, 2H), 5.13 (s, 2H), 4.06-3.98 (m, 1H), 3.12 (s, 3H),2.07-2.02 (m, 3H), 1.92-1.88 (m, 3H), 1.67 (br s, 1H), 1.34-1.26 (m,3H). Mass spectrum (API-TIS) m/z 487 (MH⁺).

Example 181-(1-(4-Fluorphenyl)-3-((3-nitrooxy)propoxy)methyl)pyrazol-5-yl)-4-methylsulfonyl)benzene18a. Methyl1-(4-fluorophenyl)-5-(4-(methylsulfonyl)phenyl)pyrazol-3-carboxylate

The title compound was prepared from the product of Example 3a (5.68 g,20 mmol) and 4-fluorophenylhydrazine hydrochloride (4.23 g, 26 mmol) inmethanol (120 mL) using the procedure of Example 10a. Separation of theregioisomers and recrystallization gave the title compound as a whitesolid (4.16 g, 55% yield). Mp 224-227° C. ¹H NMR (300 MHz, CDCl₃) δ 7.94(d, J=8.3 Hz, 2H), 7.44 (d, J=8.3 Hz, 2H), 7.33 (m, 2H), 7.17 (s, 1H),7.13 (m, 2H), 4.01 (s, 3H), 3.10 (s, 3H). Mass spectrum (API-TIS) m/z375 (MH⁺), 392 (M+18⁺). Anal. calcd. for C₁₈H₁₅FN₂O₄S: C, 57.75; H,4.04; N, 7.48. found: C, 57.66; H, 3.88; N, 7.48.

18b.1-(1-(4-Fluorophenyl)-3-(hydroxymethyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene

The title compound (0.4 g, 77% yield) was prepared from the product ofExample 18a by following the procedure for Example 5b. ¹H NMR (300 MHz,CDCl₃) δ 7.88 (d, J=8.5 Hz, 2H), 7.40 (d, J=8.5 Hz, 2H), 7.26-7.22 (m,2H), 7.07 (m, 2H), 6.62 (s, 1H), 4.80 (d, J=5.8 Hz, 2H), 3.06 (s, 3H),2.19 (d, J=5.8 Hz, 2H). Mass spectrum (API-TIS) m/z 347 (MH⁺).

18c.1-(3-(Bromomethyl)-1-(4-fluorophenyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene

The title compound (3.3 g, 82% yield) was prepared from the product ofExample 18b by following the procedure for Example 5c. ¹H NMR (300 MHz,CDCl₃) δ 7.88 (d, J=8.5 Hz, 2H), 7.40 (d, J=8.5 Hz, 2H), 7.26-7.22 (m,2H), 7.07 (m, 2H), 6.62 (s, 1H), 4.80 (d, J=5.8 Hz, 2H), 3.06 (s, 3H),2.19 (t, J=5.8 Hz, 1H). Mass spectrum (API-TIS) m/z 459 (MH⁺).

18d.1-(1-(4-Fluorophenyl)-3-((3-hydroxypropoxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene

The title compound (0.32 g, 25% yield) was prepared from the product ofExample 18c by following the procedure for Example 5d except 2-benzyloxyethanol was used instead of 3-benzyloxy propanol. ¹H NMR (300 MHz,CDCl₃) δ 7.86 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 7.24-7.21 (m,2H), 7.05 (m, 2H), 6.61 (s, 1H), 4.62 (s, 2H), 3.78 (t, J=5.8 Hz, 2H),3.76 (t, J=5.8 Hz, 2H), 3.43 (br s, 1H), 3.05 (s, 3H), 1.88 (q, J=5.8Hz, 2H). Mass spectrum (API-TIS) m/z 407 (MH⁺).

18e.1-(1-(4-Fluorophenyl)-3-((3-(nitrooxy)propoxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene

The title compound (69.3 mg, 74% yield) was prepared from the product ofExample 18d by following the procedure for Example 5e. ¹H NMR (300 MHz,CDCl₃) δ 7.88 (d, J=8.5 Hz, 2H), 7.40 (d, J=8.5 Hz, 2H), 7.27-7.22 (m,2H), 7.07 (m, 2H), 6.62 (s, 1H), 4.60 (s, 2H), 4.58 (t, J=6.1 Hz, 2H),3.68 (t, J=6.1 Hz, 2H), 3.06 (s, 3H), 2.04 (q, J=6.1 Hz, 2H). Massspectrum (API-TIS) m/z 450 (MH⁺).

Example 194-(methylsulfonyl)-1-(3-((3-(nitrooxy)butoxy)methyl)-1-phenylpyrazol-5-yl)benzene19a.4-(Methylsulfonyl)-1-(1-phenyl-3-((3-phenoxybutoxy)methyl)pyrazol-5-yl)benzene

4-Benzyloxy-1-butanol (540.6 mg, 3.1 mmol) was added to a stirredsolution of NaH (133.3 mg, 5.6 mmol) in dry THF (10 mL) and the reactionmixture stirred for 15 minutes. The product of Example 5c (1.1 g, 2.8mmol) was added and the mixture stirred overnight. The sample wasdiluted with CH₂Cl₂ (10 mL) and washed with saturated NH₄Cl and brine.The sample was dried over MgSO₄ and the solvent was evaporated underreduced pressure. The resulting residue was purified by chromatographyover silica gel eluting with 2:1 Hexanes/EtOAc followed by preparatoryplate chromatography eluting with 1:1 Hexanes/EtOAc to give the titlecompound (564.5 mg, 42% yield) as a yellow oil. ¹H NMR (300 MHz, CDCl₃)δ 7.85 (d, J=8.5 Hz, 2H), 7.40 (d, J=8.5 Hz, 2H), 7.39-7.32 (m, 5H),7.30-7.24 (m, 5H) 6.64 (s, 1H), 4.60 (s, 2H), 4.52 (s, 2H), 3.62 (t,J=5.9 Hz, 2H), 3.50 (t, J=5.9 Hz, 2H), 3.05 (s, 3H), 1.74-1.66 (m, 4H).Mass spectrum (API-TIS) m/z 491 (MH⁺).

19b.1-(3-((3-Hydroxybutoxy)methyl)-1-phenylpyrazol-5-yl)-4-(methylsulfonyl)benzene

The product of example 19a (564.5 mg, 1.2 mmol) was dissolved in EtOH(100 mL) and placed in a Parr shaker. Pd/C (1.3 g) was added and thesample flushed with nitrogen 4 times. The sample was then flushedseveral times with H₂ (25-30 psi). The hydrogenation was performed at 30psi for 30 minutes. The catalyst was removed via filtration throughCelite and washed with EtOH. The combined filtrate was evaporated underreduced pressure to give the title compound (0.23 g, 51% yield) as ayellow oil. ¹H NMR (300 MHz, CDCl₃) δ 7.83 (d, J=8.4 Hz, 2H), 7.41 (d,J=8.4 Hz, 2H), 7.37-7.35 (m, 2H), 7.28-7.25 (m, 3H), 6.65 (s, 1H), 4.64(s, 2H), 3.69-3.62 (m, 4H), 3.06 (s, 3H), 1.78-1.66 (m, 4H). Massspectrum (API-TIS) m/z 401 (MH⁺).

19c.4-(Methylsulfonyl)-1-(3-((3-(nitrooxy)butoxy)methyl)-1-phenylpyrazol-5-yl)benzene

The product of Example 19b (46.5 mg, 0.116 mmol) was dissolved inacetonitrile (3 mL) and added drop-wise to 5 ml of cold fuming HNO₃. Themixture was stirred at 0° C. for 3 hours. Water (10 mL) was addedfollowed by Na₂CO₃ until the mixture was neutralized. Methylene chloridewas added and the organics separated. The aqueous portion was extractedwith additional methylene chloride and the combined organic fractionswere washed with water, dried over MgSO₄ and the solvent was evaporatedunder reduced pressure to give the title compound (37.6 mg, 73% yield)as a yellow oil. ¹H NMR (300 MHz, CDCl₃) δ 7.89 (d, J=8.2 Hz, 2H), 7.45(d, J=8.2 Hz, 2H), 7.39-7.37 (m, 2H), 7.31-7.29 (m, 2H), 6.67 (s, 1H),4.65 (s, 2H), 4.53 (t, J=6.4 Hz, 2H), 3.66 (t, J=6.4 Hz, 2H), 3.09 (s,3H), 1.93-1.86 (m, 2H), 1.83-1.77 (m, 2H). Mass spectrum (API-TIS) m/z446 (MH⁺).

Example 204-(5-(4-Methylphenyl)-3-((3-(nitrooxy)propoxy)methyl)pyrazolyl)-benzenesulfonamide20a. Methyl 4-(4-methylphenyl)-2,4-dioxobutanoate

The title compound was prepared from dimethyloxalate (47.24 g, 400 mmol)and 4′-methylacetophenone (26.84 g, 200 mmol) using the procedure forExample 1d. Work-up and recrystallization provided the title compound aswhite needles (32.6 g, 74% yield). Mp 82-84° C. ¹H NMR (300 MHz, CDCl₃)δ 15.36 (br.s, 1H), 7.92 (d, J=8.3 Hz, 2H), 7.32 (d, J=8.3 Hz, 2H), 7.08(s, 1H), 3.96 (s, 3H), 2.46 (s, 3H). Mass spectrum (API-TIS) m/z 221(MH⁺). Anal calcd. for C₁₂H₁₂O₄: C, 65.45; H, 5.49. Found: C, 65.46; H,5.53.

20b. 4-Hydrazinobenzenesulfonamide

A stirred solution of 4-chlorobenzenesulfonamide (38.33 g, 200 mmol) andanhydrous hydrazine (31.4 mL, 1.0 mol) was heated at reflux for 30hours. After cooling to room temperature, the mixture was poured intowater (500 mL) with swirling. The resulting precipitate was collected byfiltration, washed thoroughly with water several times, air-dried, anddried under vacuum to give the title compound (35.5 g, 95% yield) as awhite solid. Mp 169-171° C. ¹H NMR (300 MHz, THF-d₈) δ 7.59 (d, J=8.8Hz, 2H), 6.77 (d, J=8.8 Hz, 2H), 6.62 (br, 1H), 5.99 (br, 2H), 3.87 (br,2H). Mass spectrum (API-TIS) m/z 188 (MH⁺).

20c. Methyl5-(4-methylphenyl)-1-(4-sulfamoylphenyl)pyrazol-3-carboxylate

To a stirred solution of the product of Example 20a (6.25 g, 28.4 mmol)in MeOH (200 mL) was added the product of Example 20b (5.31 g, 28.4mmol), followed by 12N HCl (2.4 mL). The mixture was heated at refluxfor 6 hours and then concentrated. The resulting solid was crystallizedfrom MeOH:EtOAc (1:9) to give the title compound as white plates (10.1g, 96% yield). Mp 138-139° C. ¹H NMR (300 MHz, THF-d₈) δ 7.86 (m, 2H),7.48 (m, 2H), 7.17 (s, 4H), 6.99 (s, 1H), 6.55 (br, 2H), 3.86 (s, 3H),2.34 (s, 3H). Mass spectrum (API-TIS) m/z 372 (MH⁺).

20d. 4-(3-(Hydroxymethyl)-5-(4-methylphenyl)pyrazolyl)benzenesulfonamide

To a stirred solution of the product of Example 20c (5.55 g, 14.96 mmol)in THF (500 mL) was added lithium aluminum hydride (1.0 M in THF, 37 mL,37 mmol) drop-wise. After stirring at room temperature for 3 hours, themixture was poured onto crushed ice, acidified with 12N HCl (20 mL),extracted with EtOAc, dried over Na₂SO₄, filtered, and concentrated. Theresulting solid was crystallized from EtOAc:Hexane (2:1) to give thetitle compound as white prisms (4.60 g. 89% yield). Mp 130° C. ¹H NMR(300 MHz, THF-d₈) δ 7.79 (d, J=8.5 Hz, 2H), 7.34 (d, J=8.5 Hz, 2H), 7.14(d, J=8.0 Hz, 2H), 7.07 (d, J=8.0 Hz, 2H), 6.50 (s, 1H), 5.4 (br s, 2H),4.79 (s, 2H), 2.36 (s, 3H), 2.1 (br s, 1H). Mass spectrum (API-TIS) m/z344 (MH⁺).

20e. (5-(4-Methylphenyl)-1-(4-sulfamoylphenyl)pyrazol-3-yl)methylmethylsulfonate

To a stirred solution of the product of Example 20d (4.79 g, 13.97 mmol)and N,N-diisopropylethylamine (2.96 mL, 17 mmol) in THF (120 mL) wasadded methanesulfonyl chloride (1.08 mL, 14 mmol). After stirring atroom temperature for 1 hour, the mixture was poured into 2N HCl,extracted with EtOAc, dried over Na₂SO₄, filtered, and concentrated togive the title compound as a white foam (5.21 g), which was used for thenext step without further purification. ¹H NMR (300 MHz, CDCl₃) δ 7.78(d, J=8.5 Hz, 2H), 7.30 (d, J=8.5 Hz, 2H), 7.12 (d, J=8.0 Hz, 2H), 7.05(d, J=8.0 Hz, 2H), 6.63 (s, 1H), 5.8 (br s, 2H), 5.34 (s, 2H), 3.09 (s,3H), 2.33 (s, 3H). Mass spectrum (API-TIS) m/z 422 (MH⁺).

20f.4-(3-((3-Hydroxypropoxy)methyl)-5-(4-methylphenyl)pyrazolyl)benzenesulfonamide

Sodium (0.66 g, 28.7 mmol) was stirred in 1,3-propanediol (8 mL) whileheating (50° C.) until complete dissolution. The product of Example 20e(1.26 g, 3.00 mmol) in THF (15 mL) was added, and the resulting solutionwas heated at reflux for 2 hours. The mixture was poured into ice-cooledaqueous NH₄Cl, extracted with EtOAc, washed with brine, dried overNa₂SO₄, filtered, and concentrated. Chromatography of the residue oversilica gel eluting with a 0-5% gradient MeOH in CHCl₃) furnished thetitle compound as a white solid (1.08 g, 94% yield over two steps). Mp85-86° C. ¹H NMR (300 MHz, CDCl₃) δ 7.73 (d, J=8.6 Hz, 2H), 7.25 (d,J=8.6 Hz, 2H), 7.09 (d, J=8.2 Hz, 2H), 7.03 (d, J=8.2 Hz, 2H), 6.47 (s,1H), 6.15 (br s, 2H), 4.59 (s, 2H), 3.72 (m, 4H), 3.25 (br, 1H), 2.31(s, 3H), 1.83 pentet, J=5.8 Hz, 2H). Mass spectrum (API-TIS) m/z 402(MH⁺).

20g.4-(5-(4-Methylphenyl)-3-((3-(nitrooxy)propoxy)methyl)pyrazolyl)benzenesulfonamide

A mixture of 90% HNO₃ (1.17 mL, 25 mmol) and Ac₂O (7 mL) was stirred at−10° C. (ice-MeOH bath) for 30 min. The product of Example 20f (2.09 g,5.21 mmol) in THF (12 mL) was added. After being stirred at −10° C. for20 minutes, the mixture was poured into ice containing aqueous Na₂CO₃,extracted with EtOAc, washed with brine, dried over Na₂SO₄, filtered,and concentrated. Chromatography of the residue over silica gel elutingwith EtOAc:Hexane 2:1 afforded the title compound as a tan solid (1.61g, 69% yield). Mp 62° C. ¹H NMR (300 MHz, CDCl₃) δ 7.76 (d, J=8.7 Hz,2H), 7.32 (d, J=8.7 Hz, 2H), 7.13 (d, J=8.1 Hz, 2H), 7.08 (d, J=8.1 Hz,2H), 6.51 (s, 1H), 5.75 (br s, 2H), 4.62 (s, 2H), 4.60 (t, J=6.3 Hz,2H), 3.69 (t, J=6.0 Hz, 2H), 2.34 (s, 3H), 2.07-2.02 (m, 2H); ¹³C NMR(75 MHz, CDCl₃) δ 151.3, 144.7, 142.8, 140.6, 140.0, 129.5, 128.6,127.2, 126.7, 124.9, 108.0, 70.5, 66.4, 66.2, 27.2, 21.2. Mass spectrum(API-TIS) m/z 447 (MH⁺).

Example 211-(3-((1E)-4-(Nitrooxy)but-1-enyl)-1-cyclohexylpyrazol-5-yl)-4-(methylsulfonyl)benzene21a.1-((3E)-4-(1-Cyclohexyl-5-(4-methylthiophenyl)pyrazol-3-yl)but-3-enyloxy)-1,1,2,2-tetramethyl-1-silapropane

n-Butyl lithium (2.25 mL of 2.5 M solution in hexane, 0.36 g, 5.6 mmol),was added drop-wise to solution of phosphonium salt((3-((1,1-dimethylethyl)-dimethylsilyl)-oxy)propyl)-triphenylphosphoniumbromide) (2.45 g, 4.76 mmol) in THF (13 mL) at −78° C. The resultantsolution was stirred at −78° C. for 1 hour. To this solution product ofthe Example 4c (1.3 g, 4.3 mmol) in THF (13 mL) was added drop-wise andthe stirring continued at −78° C. for 1 hour. The reaction mixture wasgradually warmed to room temperature and stirred at room temperature for24 hour. Water was added and extracted with EtOAc which was then washedwith water, dried and filtered. The residue, after evaporation of thesolvent, was purified by chromatography over silica gel eluting with0.5:10 EtOAc:Hex to give pure Z-isomer (1.2 g, 61% yield) as a colorlessoil and E-isomer (0.1 g, 5% yield). E-isomer: ¹H NMR (300 MHz, CDCl₃) δ7.22-7.35 (m, 4H), 6.51 (d, J=16.1 Hz, 1H), 6.26 (s, 1H), 6.12-6.25 (m,1H), 3.92-4.08 (m, 1H), 3.72 (t, J=7.10 Hz, 2H), 2.53 (s, 3H), 2.37-2.48(m, 2H), 1.56-2.10 (m, 7H), 1.16-1.30 (m, 3H), 0.91 (s, 9H), 0.07 (s,6H). ¹³C NMR (75 MHz, CDCl₃) δ 149.8, 143.3, 139.3, 129.5, 128.1, 127.9,126.5, 124.4, 102.1, 63.3, 57.8, 36.7, 33.5, 26.1, 25.8, 25.3, 18.5,15.6, −5.0. mass spectrum (API-TIS) m/z 457 (MH⁺).

21b.1-(3-((1E)-4-(Hydroxy)but-1-enyl)-1-cyclohexylpyrazol-5-yl)-4-methylsulfonyl)benzene

The title compound was prepared as a white solid from the product ofExample 21a by following the procedure for Example 12d. Mp 129-130° C.¹H NMR (300 MHz, CDCl₃) δ 8.04 (d, J=8.2 Hz, 2H), 7.55 (d, J=8.2 Hz,2H), 6.07 (d, J=16.0 Hz, 1H), 6.37 (s, 1H), 6.16-6.30 (m, 1H), 3.89-4.08(m, 1H), 3.77 (q, J=6.0 Hz, 2H), 3.13 (s, 3H), 2.49 (q, J=6.5 Hz, 2H),1.42-2.12 (m, 7H), 1.10-1.37 (m, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 149.9,141.8, 140.6, 136.8, 129.9, 128.2, 128.1, 125.1, 103.4, 62.2, 58.4,44.7, 36.5, 33.5, 25.8, 25.2. mass spectrum (API-TIS) m/z 375 (MH⁺).Anal. Calcd. for C₂₀H₂₆N₂O₃S.¼ mol H₂O: C, 63.38; H, 7.04; N, 7.39; S,8.46. Found: C, 63.35; H, 7.13; N, 7.13; S, 8.44.

21c.1-(3-((1E)-4-(Nitrooxy)but-1-enyl)-1-cyclohexylpyrazol-5-yl)-4-(methylsulfonyl)benzene

The title compound was prepared as a white foam from the product ofExample 21b by following the procedure for Example 1h. ¹H NMR (300 MHz,CDCl₃) δ 8.05 (dd, J=1.5 and 8.4 Hz, 2H), 7.57 (dd, J=1.7 and 6.7 Hz,2H), 6.57 (d, J=16.0 Hz, 1H), 6.37 (s, 1H), 6.09-6.23 (m, 1H), 4.57 (t,J=6.7 Hz, 2H), 3.90-4.12 (m, 1H), 3.13 (s, 3H), 2.55-2.68 (m, 2H),1.60-2.12 (m, 7H), 1.12-1.35 (m, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 149.3,141.9, 140.6, 136.6, 129.9, 128.0, 125.9, 125.1, 103.5, 72.3, 58.4,44.6, 33.5, 31.7, 30.5, 25.7, 25.1. mass spectrum (API-TIS) m/z 420(MH⁺). Anal. Calcd. for C₂₀H₂₅N₃O₅S: C, 57.26; H, 6.01; N, 10.02. Found:C, 56.98; H, 6.00; N, 9.75.

Example 221-(1-Cyclohexyl-5-(4-(methylsulfonyl)pyrazol-3-yl)-6-(nitrooxy)hexan-2-one22a.(1-Cyclohexyl-5-(4-(methylthiophenyl)pyrazol-3-yl)-N-methoxy-N-methylcarboxamide

The title compound was prepared as a white solid from the product ofExample 4a by following the procedure for Example 3c. Mp 80-82° C. ¹HNMR (300 MHz, CDCl₃) δ 7.34 (d, J=6.4 Hz, 2H), 7.27 (d, J=8.0 Hz, 2H),6.71 (s, 1H), 4.05-4.20 (m, 1H), 3.84 (s, 3H), 3.48 (s, 3H), 2.54 (s,3H), 1.80-2.10 (m, 6H), 1.56-1.70 (m, 1H), 1.17-1.32 (m, 3H). ¹³C NMR(75 MHz, CDCl₃) δ 144.2, 142.9, 139.9, 129.5, 126.9, 126.4, 108.6, 61.6,58.4, 33.4, 25.6, 25.2, 15.5. Mass spectrum (API-TIS) m/z 360 (MH⁺).Anal. Calcd. for C₁₉H₂₅N₃O₂S: C, 63.48; H, 7.01; N, 11.69. Found: C,63.72; H, 7.05; N, 11.75.

22b.1-(1-Cyclohexyl-5-(4-methylthiophenyl)-pyrazol-3-yl)-6-(1,1,2,2-tetramethyl-1-silapropoxy)hexanone-1-one

To a solution of the product of Example 22a (6.0 g, 16.7 mmol) in THF(40 mL) was added drop-wise the Grignard reagent prepared from3-bromo-1-(1,1,2,2-tetramethyl-1-silapropoxy)pentane (6.15 g, 21.8 mmol)and magnesium turnings (1.1 g, 46.0 mmol) in THF (40 mL) at roomtemperature under nitrogen. The reaction mixture was stirred at roomtemperature for 5 hours, and then quenched by the addition of saturatedaqueous NH₄Cl at 0° C. The reaction mixture was diluted with EtOAc andthe layers were separated. The aqueous layer was extracted with EtOAcand the combined organic layers were washed with water, dried (Na₂SO₄)and filtered. The residue obtained after evaporation of the solvent waspurified by chromatography over silica gel eluting with 1:10 to 2:10EtOAc:Hexane to give the title compound (3.79 g, 48% yield) as acolorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.33 (d, J=8.4 Hz, 2H), 7.26(d, J=8.4 Hz, 2H), 6.71 (s, 1H), 4.00-4.18 (m, 1H), 3.63 (t, J=6.5 Hz,2H), 3.03 (t, J=7.4 Hz, 2H), 2.54 (s, 3H), 1.82-2.13 (m, 7H), 1.76 (p,J=7.6 Hz, 2H), 1.52-1.64 (m, 2H), 1.36-1.52 (m, 2H), 1.20-1.36 (m, 3H),0.91 (s, 9H), 0.06 (s, 6H). ¹³C NMR (75 MHz, CDCl₃) δ 197.1, 150.1,143.9, 140.1, 129.5, 126.8, 126.4, 106.3, 63.3, 58.5, 38.7, 33.4, 32.9,26.1, 25.8, 25.6, 25.2, 24.5, 18.5, 15.5, −5.1. Mass spectrum (API-TIS)m/z 501 (MH⁺). Anal. calcd. for C₂₈H₄₄N₂O₂SSi: C, 67.15; H, 8.86; N,5.59. Found: C, 67.14; H, 8.68; N, 5.59.

22c.1-(1-Cyclohexyl-5-(4-(methylsulfonyl)phenyl)-pyrazol-3-yl)-6-hydroxyhexan-1-one

The title compound was prepared as a white solid from the product ofExample 22b by following the procedure for Example 12d. Mp 125-127° C.¹H NMR (300 MHz, CDCl₃) δ 8.06 (d, J=8.4 Hz, 2H), 7.56 (d, J=8.4 Hz,2H), 6.80 (s, 1H), 3.98-4.12 (m, 1H), 3.68 (q, J=6.3 Hz, 2H), 3.13 (s,3H), 3.07 (t, J=7.3 Hz, 2H), 1.83-2.14 (m, 7H), 1.79 (p, J=7.5 Hz, 2H),1.60-1.72 (m, 3H), 1.40-1.57 (m, 2H), 1.18-1.37 (m, 3H). ¹³C NMR (75MHz, CDCl₃) δ 196.8, 150.4, 142.4, 141.0, 135.9, 130.0, 128.1, 107.2,62.9, 59.1, 44.6, 38.6, 33.4, 32.7, 25.6, 25.5, 25.1, 24.1. Massspectrum (API-TIS) m/z 419 (MH⁺), 401 (M-OH). Anal. calcd. forC₂₂H₃₀N₂O₄S: C, 63.13; H, 7.22; N, 6.69. Found: C, 63.19; H, 7.08; N,6.67.

22d.1-(1-Cyclohexyl-5-(4-(methylsulfonyl)pyrazol-3-yl)-6-(nitrooxy)hexan-1-one

The title compound was prepared as a white solid from the product ofExample 22c by following the procedure for Example 1h. Mp 111-113° C. ¹HNMR (300 MHz, CDCl₃) δ 8.07 (dd, J=1.9 and 8.5 Hz, 2H), 7.57 (d, J=8.4Hz, 2H), 6.81 (s, 1H), 4.48 (t, J=6.7 Hz, 2H), 3.98-4.15 (m, 1H), 3.14(s, 3H), 3.07 (t, J=7.3 Hz, 2H), 1.67-2.16 (m, 8H), 1.81 (p, J=8.0 Hz,2H), 1.45-1.61 (m, 3H), 1.19-1.38 (m, 3H). ¹³C NMR (75 MHz, CDCl₃) δ196.2, 150.2, 142.5, 141.0, 135.8, 130.0, 128.1, 107.1, 73.3, 59.0,44.5, 38.2, 33.4, 26.7, 25.5, 25.4, 25.0, 23.8. Mass spectrum (API-TIS)m/z 464 (MH⁺). Anal. calcd. for C₂₂H₂₉N₃O₆S: C, 57.00; H, 6.31; N, 9.06.Found: C, 57.07; H, 6.24; N, 8.97.

Example 231-(5-(4-(Methylsulfonyl)phenyl)-1-(4-(trifluoromethyl)phenyl)pyrazol-3-yl)-4-(nitrooxy)butan-1-one23a. Methyl5-(4-methylthiophenyl)-1-(4-(trifluoromethyl)phenyl)pyrazol-3-carboxylate

The title compound was prepared from the product of Example 1d (5.0 g,20 mmol) and 4-(trifluoromethyl)phenylhydrazine hydrochloride (4.58 g,26 mmol) in acetic acid (120 mL) in a manner similar to Example 7a.Work-up and recrystallization provided the title compound as a whitesolid (4.05 g, 52% yield). Mp 108-110° C. ¹H NMR (300 MHz, CDCl₃) δ 7.66(d, J=8.5 Hz, 2H), 7.51 (d, J=8.5 Hz, 2H), 7.23 (d, J=8.5 Hz, 2H), 7.15(d, J=8.5 Hz, 2H), 7.06 (s, 1H), 4.01 (s, 3H), 2.52 (s, 3H). Massspectrum (API-TIS) m/z 393 (MH⁺). Anal. calcd. for C₁₉H₁₅F₃N₂O₂S: C,58.16; H, 3.85; N, 7.14. found: C, 58.26; H, 3.73; N, 7.10.

23b.N-Methoxy-N-methyl(5-(4-methylthiophenyl)-1-(4-(trifluoromethyl)phenyl)-pyrazolyl)carboxamide

The title compound was prepared from the product of Example 23a byfollowing the procedure for Example 3c. Mp 142-144° C. ¹H NMR (300 MHz,CDCl₃) δ 7.62 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.5 Hz, 2H) 7.21 (dd, J=2.1and 6.5 Hz, 2H), 7.14 (dd, J=2.1 and 6.5 Hz, 2H), 6.97 (s, 1H), 3.86 (s,3H), 3.50 (br s, 3H), 2.50 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 146.1,143.3, 140.0, 138.1, 133.6, 129.0 (J_(C-F)=9.4 Hz), 126.4, 125.9, 125.7,110.1, 61.6, 34.0, 15.1. Mass spectrum (API-TIS) m/z 422 (MH⁺). Anal.calcd. for C₂₀H₁₈F₃N₃O₂S: C, 57.00; H, 4.31; N, 9.97. Found: C, 56.78;H, 4.12; 9.76.

23c.1-(5-(4-Methylthiophenyl)-1-(4-(trifluoromethyl)phenyl)pyrazol-3-yl)-4-(1,1,2,2-tetramethyl-1-silapropoxy)butan-1-one

The title compound was prepared as a white solid from the product ofExample 23b by following the procedure for Example 3d. Mp 102-103° C. ¹HNMR (300 MHz, CDCl₃) δ 7.59 (d, J=8.6 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H)7.15 (d, J=8.4 Hz, 2H), 7.07 (d, J=8.4 Hz, 2H), 6.93 (s, 1H), 3.68 (t,J=6.3 Hz, 2H), 3.11 (t, J=7.3 Hz, 2H), 2.44 (s, 3H), 1.88-2.05 (m, 2H),0.84 (s, 9H), 0.01 (s, 6H). ¹³C NMR (75 MHz, CDCl₃) δ196.4, 152.1,144.7, 142.5, 140.7, 130.1 (J_(C-F)=32.9 Hz), 129.2, 126.4 (J_(C-F)=3.7Hz), 126.2, 125.8, 125.6, 125.4, 108.5, 62.6, 35.4, 27.5, 26.1, 18.5,15.3, −5.2. Mass spectrum (API-TIS) m/z 535 (MH⁺). Anal. calcd. forC₂₇H₃₃F₃N₂O₂SSi: C, 60.65; H, 6.22; N, 5.24. Found: C, 60.49; H, 6.13;5.09.

23d.4-Hydroxy-1-(5-(4-(methylsulfonyl)phenyl)-1-(4-(trifluoromethyl)-phenyl)pyrazol-3-yl)butan-1-one

The title compound was prepared as a white solid from the product ofExample 23c by following the procedure for Example 12d. Mp 60-63° C. ¹HNMR (300 MHz, CDCl₃) δ 7.95 (dd, J=1.7 and 6.7 Hz, 2H), 7.69 (d, J=8.4Hz, 2H), 7.42-7.47 (m, 4H), 7.12 (s, 1H), 3.74 (t, J=5.9 Hz, 2H), 3.24(t, J=7.0 Hz, 2H), 3.09 (s, 3H), 1.97-2.12 (m, 2H), 1.85-1.97 (br s,1H). ¹³C NMR (75 MHz, CDCl₃) δ 196.4, 152.3, 143.2, 141.9, 141.3, 134.7,130.8, 129.7, 128.2, 126.9 (J_(C-F)=3.6 Hz), 125.6, 109.7, 62.4, 44.5,35.6, 27.2. Mass spectrum (API-TIS) m/z 453 (MH⁺), 435 (M-OH). Anal.calcd. for C₂₁H₁₉F₃N₂O₄S: C, 55.75; H, 4.23; N, 6.19. Found: C, 55.59;H, 4.14; 5.91.

23e.1-(5-(4-(Methylsulfonyl)phenyl)-1-(4-(trifluoromethyl)phenyl)pyrazol-3-yl)-4-(nitrooxy)butan-1-one

The title compound was prepared as a white solid from the product ofExample 23d by following the procedure for Example 1h. Mp 152-154° C. ¹HNMR (300 MHz, CDCl₃) δ 7.95 (d, J=8.3 Hz, 2H), 7.70 (d, J=8.6 Hz, 2H),7.42-7.47 (m, 4H), 7.13 (s, 1H), 4.59 (t, J=6.3 Hz, 2H), 3.26 (t, J=7.0Hz, 2H), 3.10 (s, 3H), 2.23 (p, J=6.7 Hz, 2H). ¹³C NMR (75 MHz, CDCl₃) δ194.3, 151.9, 143.3, 141.8, 141.3, 134.6, 131.3, 129.7, 128.2, 126.9(J_((C-F))=3.8 Hz), 125.6, 125.4, 109.6, 72.6, 44.5, 34.7, 21.3. Massspectrum (API-TIS) m/z 498 (MH⁺), 515 (MNa⁺). Anal. calcd. forC₂₁H₁₈F₃N₃O₆S: C, 50.71; H, 3.65; N, 8.45. Found: C, 50.60; H, 3.49;8.20.

Example 241-(1-(4-Methoxyphenyl)-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-4-(nitrooxy)butan-1-one24a. Methyl1-(4-methoxyphenyl)-5-(4-methylthiophenyl)pyrazole-3-carboxylate

The title compound was prepared from the product of Example 1d (5.05 g,20 mmol) and 4-methoxyphenylhydrazine hydrochloride (4.54 g, 26 mmol) inmethanol (120 mL) by following the procedure of Example 8a. Separationof the regioisomers and recrystallization gave the title compound aswhite needles (5.45 g, 15.4 mmol, 77% yield. Mp 106-108° C.; ¹H NMR (300MHz, CDCl₃) δ 7.27 (d, J=8.9 Hz, 2H), 7.19 (d, J=8.6 Hz, 2H), 7.14 (d,J=8.6 Hz, 2H), 7.04 (s, 1H), 6.89 (d, J=8.9 Hz, 2H), 3.99 (s, 3H), 3.85(s, 3H), 2.50 (s, 3H). Mass spectrum (API-TIS) m/z 355 (MH⁺); Anal.calcd. for C₁₉H₁₈N₂O₃S: C, 64.39; H, 5.12; N, 7.90. found: C, 64.39; H,5.05; N, 7.79.

24b.N-Methoxy-(1-(4-methoxyphenyl)-5-(4-methylthiophenyl)-pyrazol-3-yl)-N-methylcarboxamide

The title compound was prepared as a white solid from the product ofExample 24a by following the procedure for Example 3c. Mp 131-133° C. ¹HNMR (300 MHz, CDCl₃) δ 7.25-7.29 (m, 2H), 7.14-7.20 (m, 4H), 6.98 (s,1H), 6.89 (d, J=8.2 Hz, 2H), 3.87 (s, 3H), 3.84 (s, 3H), 3.53 (br s,3H), 2.49 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 159.4, 145.7, 143.3, 139.6,133.1, 129.1, 126.9, 126.4, 126.1, 114.3, 109.7, 61.7, 55.6, 34.0, 15.4.mass spectrum (API-TIS) m/z 384 (MH⁺). Anal. Calcd. for C₂₀H₂₁N₃O₃S: C,62.64; H, 5.52; N, 10.96. Found: C, 62.44; H, 5.29; N, 10.75.

24c.1-(1-(4-Methoxyphenyl)-5-(4-methylthiophenyl)pyrazol-3-yl)-4-(1,1,2,2-tetramethyl-1-silapropoxy)butan-1-one

The title compound was prepared as a white solid from the product ofExample 24b by following the procedure for Example 3d. mp 51-53° C. ¹HNMR (300 MHz, CDCl₃) δ 7.24 (d, J=8.8 Hz, 2H), 7.16 (d, J=8.4 Hz, 2H),7.11 (d, J=8.5 Hz, 2H), 6.96 (s, 1H), 6.89 (d, J=8.8 Hz, 2H), 3.83 (s,3H), 3.72 (t, J=6.4 Hz, 2H), 3.15 (t, J=7.3 Hz, 2H), 2.47 (s, 3H), 1.99(p, J=6.9 Hz, 2H), 0.89 (s, 9H), 0.05 (s, 6H). ¹³C NMR (75 MHz, CDCl₃) δ196.6, 159.5, 151.3, 144.4, 139.8, 133.0, 129.1, 126.9, 126.3, 126.0,114.4, 107.3, 62.7, 55.6, 35.3, 27.5, 26.1, 18.4, 15.3, −5.2. massspectrum (API-TIS) m/z 497 (MH⁺). Anal. Calcd. for C₂₇H₃₆N₂O₃SSi: C,65.29; H, 7.30; N, 5.64. Found: C, 65.06; H, 7.40; N, 5.52.

24d.4-Hydroxy-1-(1-(4-methoxyphenyl)-5-(4-(methylsulfonyl)phenyl)-pyrazol-3-yl)butan-1-one

The title compound was prepared as a white solid from the product ofExample 24c by following the procedure for Example 3e. Mp 125-127° C. ¹HNMR (300 MHz, CDCl₃) δ 7.89 (d, J=8.4 Hz, 2H), 7.40 (d, J=6.8 Hz, 2H),7.22 (dd, J=2.1 and 8.9 Hz, 2H), 7.10 (s, 1H), 6.91 (dd, J=2.1 and 8.9Hz, 2H), 3.85 (s, 3H), 3.73 (t, J=6.0 Hz, 2H), 3.23 (t, J=6.9 Hz, 2H),3.07 (s, 3H), 2.04 (p, J=6.9 Hz, 2H). ¹³C NMR (75 MHz, CDCl₃) δ 196.6,160.0, 151.4, 143.0, 140.5, 135.0, 132.1, 129.5, 127.8, 126.9, 114.7,108.4, 62.2, 55.7, 44.4, 35.5, 27.4. mass spectrum (API-TIS) m/z 415(MH⁺), 397 (M-OH). Anal. Calcd. for C₂₁H₂₂N₂O₅S: C, 60.86; H, 5.35; N,6.76. Found: C, 60.66; H, 5.27; N, 6.59.

24e.1-(1-(4-Methoxyphenyl)-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl-4-(nitrooxy)butan-1-one

The title compound was prepared as a white solid from the product ofExample 24d by following the procedure for Example 1h. Mp 132-134° C. ¹HNMR (300 MHz, CDCl₃) δ 7.89 (d, J=8.3 Hz, 2H), 7.41 (d, J=8.3 Hz, 2H),7.20-7.27 (m, 2H), 7.10 (s, 1H), 6.91-6.95 (m, 2H), 4.58 (t, J=6.4 Hz,2H), 3.85 (s, 3H), 3.26 (t, J=7.1 Hz, 2H), 3.07 (s, 3H), 2.21 (p, J=6.7Hz, 2H). ¹³C NMR (75 MHz, CDCl₃) δ 194.5, 160.1, 151.1, 143.1, 140.6,135.1, 132.2, 129.5, 127.9, 127.0, 114.8, 108.4, 72.6, 55.8, 44.5, 34.6,21.3. mass spectrum (API-TIS) m/z 460 (MH⁺). Anal. Calcd. forC₂₁H₂₁N₃O₇S: C, 54.90; H, 4.61; N, 9.15. Found: C, 54.63; H, 4.43; N,8.97.

Example 251-(3-((1Z)-4-(nitrooxy)but-1-enyl)-5-(3-pyridyl)pyrazolyl)-4-(methylsulfonyl)benzene25a. Methyl 2,4-dioxo-4-(3-pyridyl)butanoate

Sodium methoxide (5.4 g, 100 mmol) and dimethyloxalate (11.8 g, 100mmol) were dissolved in anhydrous methanol (700 mL) and stirred at roomtemperature under nitrogen until a suspension was formed. To thismixture, 3-acetylpyridine (5.5 mL, 50 mmol) was added and the stirringwas continued for 3 days at room temperature. The reaction was quenchedwith enough 5% aqueous KHSO₄ until all solids have dissolved. Themethanol was removed under reduced pressure, and the residue wasextracted with ethyl acetate (3×200 mL). The combined organic layerswere washed with water (2×200 mL), brine and dried (NaSO₄) followed bythe removal of solvent under reduced pressure to give the title compound(8.67 g, 84% yield) as a yellow solid. ¹H NMR (CDCl₃, 300 MHz) δ9.21-9.20 (m, 1H), 8.84-8.82 (m, 1H), 8.30-8.26 (m, 1H), 7.50-7.45 (m,1H), 7.08 (s, 1H), 3.96 (s, 3H). ¹³C NMR (CDCl₃, 75 MHz) δ 188.5, 170.4,162.2, 153.9, 149.0, 135.2, 130.5, 123.8, 98.0, 53.3. mass spectrum(APIMS) m/z 208 (M+1)⁺.

25b. Methyl1-(4-(methylsulfonyl)phenyl)-5-(3-pyridyl)pyrazol-3-carboxalate

A mixture of the product of Example 25a (295 mg, 1.4 mmol) and4-methylsulfonyl phenylhydrazine hydrochloride (528 mg, 2.8 mmol) wasdissolved in anhydrous methanol (10 mL) and refluxed (70° C.) overnightunder nitrogen. Solvent was removed under reduced pressure and theresidue was partitioned with ethyl acetate and saturated aqueoussolution of sodium bicarbonate (50 mL each). The organic layer waswashed with water, brine and dried (NaSO₄). The solvent was removedunder reduced pressure and purification by silica gel flash columnchromatography with 1% methanol in dichloromethane yielded the titlecompound (350 mg, 69% yield) as an orange colored solid. ¹H NMR (CDCl₃,300 MHz) δ 8.66-8.65 (m, 1H), 8.58-8.57 (m, 1H), 7.99-7.96 (m, 2H),7.59-7.54 (m, 3H), 7.37-7.33 (m, 1H) 7.16 (s, 1H), 3.99 (s, 3H), 3.10(s, 3H). ¹³C NMR (CDCl₃, 75 MHz) δ161.9, 150.3, 149.1, 145.2, 142.9,141.5, 140.3, 135.8, 128.6, 125.8, 125.0, 123.5, 111.4, 52.3, 44.3. LRMS(APIMS) m/z 715 (2M+1)⁺, 358 (M+1)⁺.

25c.1-(3-(Hydroxymethyl)-5-(3-pyridyl)pyrazoyl)-4-(methylsulfonyl)benzene

The product of Example 25b (600 mg, 1.7 mmol) was dissolved in anhydrousdichloromethane (50 mL). To this solution, DIBAL-H (1M in toluene, 3.4mL, 3.4 mmol) was added drop-wise under nitrogen and stirred at roomtemperature for 15 min. The reaction was quenched with saturatedammonium chloride, filtered and the layers were separated. The organiclayer was washed with water (1×50 mL), brine and dried (NaSO₄) and thesolvent was removed under reduced pressure. Purification by silica gelflash column chromatography with 3% methanol in dichloromethane yieldedthe title compound (310 mg, 57% yield) as a white solid. ¹H NMR (CDCl₃,300 MHz) δ 8.64-8.61 (m, 1H), 8.57-8.56 (m, 1H), 7.94-7.89 (m, 2H),7.53-7.45 (m, 3H), 7.38-7.27 (m, 1H), 6.65 (s, 1H), 4.81 (s, 2H), 3.07(s, 3H), 2.69 (br s, 1H). ¹³C NMR (CDCl₃, 75 MHz) δ 154.6, 150.0, 149.1,143.6, 141.0, 139.2, 135.9, 128.6, 126.2, 125.1, 123.6, 108.5, 58.8,44.5. mass spectrum (APIMS) m/z 659 (2M+1)⁺, 330 (M+1)⁺.

25d. 1-(4-(Methylsulfonyl)phenyl)-5-(3-pyridyl)pyrazol-3-carbaldehyde

The product of Example 25c (200 mg, 0.6 mmol) was dissolved in anhydrousdichloromethane (30 mL) and alumina (1 g) was added and stirred undernitrogen. Pyridinium chlorochromate (380 mg, 1.8 mmol) was added andcontinued stirring for 20 min. The reaction mixture was filtered, thenwashed with saturated aqueous solution of sodium bicarbonate (3×30 mL),water (1×30 mL), brine (1×30 mL), dried (NaSO₄), filtered and solventremoved under reduced pressure. The product was purified on silica gelflash column chromatography with 3% methanol in dichloromethane to givethe pure title compound (80 mg, 41% yield) as a solid. ¹H NMR (CDCl₃,300 MHz) δ 10.10 (s, 1H), 8.69-8.67 (m, 1H), 8.58-8.57 (m, 1H), 8.02 (s,1H), 7.99 (s, 1H), 7.61-7.52 (m, 3H), 7.37-7.34 (m, 1H), 7.12 (s, 1H),3.10 (s, 3H). mass spectrum (APIMS) m/z 328 (M+1)⁺.

25e.1-(3-((1Z)-4-Hydroxybut-1-enyl)-5-(3-pyridinyl)pyrazolyl)-4-(methylsulfonyl)benzene

1-t-Butyldimethylsilyloxypropyl-3-triphenylphosphonium bromide (310 mg,0.6 mmol, 2.5 eq.) and anhydrous THF (10 mL) was stirred and cooled to−78° C. under nitrogen. To this suspension, n-BuLi (1.6 M in hexanes,300 μL, 2 mmol) was added and stirred for 20 minutes until the darkorange color was observed. To this solution the product of Example 25d(80 mg, 0.24 mmol) dissolved in anhydrous THF (5 mL) was added andstirred for 30 minutes. The reaction mixture was stirred for another 2hours at room temperature. The reaction was quenched with saturatedammonium chloride (3 mL) and layers were separated. The aqueous layerwas diluted until all solids dissolved and further extracted with ethylacetate (2×30 mL). The combined organic layers were washed with brineand dried (NaSO₄), filtered and solvent removed under reduced pressure.The product was purified by chromatography over silica gel and then itwas dissolved in THF and tetrabutyl ammonium fluoride (1M, 2 mL, 2 mmol)was added and mixture stirred under nitrogen overnight. The solvent wasremoved under reduced pressure, and the residue was partitioned withdichloromethane and water (30 mL each) and layers separated. The organiclayer was washed with brine and dried (NaSO₄), filtered and solventremoved under reduced pressure. The product was purified by silica gelflash column chromatography using 1% methanol in dichloromethane toyield the title compound (40 mg, 52% yield) as a colorless foam. ¹H NMR(CDCl₃, 300 MHz) δ 8.64 (d, J=3.8 Hz, 1H), 8.59 (br s, 1H), 7.92 (d,J=8.6 Hz, 2H), 7.55-7.47 (m, 3H), 7.37-7.32 (m, 1H), 6.64 (s, 1H), 6.53(d, 1H, J=11.6 Hz), 6.02-5.93 (m, 1H), 3.85 (t, J=6.2, 2H), 3.07 (s,1H), 2.87-2.80 (m, 2H). ¹³C NMR (CDCl₃, 75 MHz) δ 151.0, 149.9, 149.1,143.5, 140.5, 139.1, 135.9, 132.2, 128.6, 126.0, 124.9, 123.5, 121.8,110.5, 62.0, 44.4, 32.6. mass spectrum (APIMS) m/z 370 (M+1)⁺.

25f.1-(3-((1Z)-4-(Nitrooxy)but-1-enyl)-5-(3-pyridyl)pyrazolyl)-4-(methylsulfonyl)benzene

The product of Example 25e (40 mg, 0.11 mmol) was dissolved in a mixtureof ethyl acetate (3 mL) and dichloromethane (2 mL). The solution wascooled to 0° C. In a separate flask, acetic anhydride (620 μL) andfuming nitric acid (190 μL) was mixed together at 0° C. The Ac₂O/HNO₃mixture (270 μL) was added to the solution of starting material andstirred at 0° C. for 10 min and at room temperature for 5 min. Thereaction was quenched by pouring over crushed ice, layers separated andthe aqueous layer was further extracted with ethyl acetate (2×25 mL).The combined organic layers were washed with water (3×25 mL), brine(1×25 mL) and dried (NaSO₄). The solution was filtered and solvent wasremoved under reduced pressure to give the title compound (38 mg, 84%yield) as a colorless foam. ¹H NMR (CDCl₃, 300 MHz) δ 8.70 (br s, 2H),7.98 (d, J=8.6 Hz, 2H), 7.67-7.65 (m, 1H), 7.55 (d, J=8.6 Hz, 2H), 7.46(br s, 1H), 6.66 (s, 1H), 6.56 (d, J=12 Hz, 1H), 5.94-5.85 (m, 1H), 4.69(t, J=6.8, 2H), 3.16-3.10 (m, 2H), 3.13 (s, 3H). ¹³C NMR (CDCl₃, 75 MHz)δ 155.2, 148.9, 148.2, 143.5, 139.9, 139.4, 136.9, 128.7, 128.5, 125.0,122.6, 110.9, 72.2, 44.5, 27.3. Mass spectrum (APIMS) m/z 415 (M+1)⁺.

Example 264-(5-(3-Nitrooxy)propoxy)-methyl)-3-phenylisoxazol-4-yl)benzenesulfonamide26a.4-(5-(3-Hydroxypropoxy)methyl)-3-phenylisoxazol-4-yl)benzenesulfonamide

Sodium (0.50 g, 22 mmol) was dissolved in 1,3-propanediol (10 mL) and tothis was added a solution of4-(5-(chloromethyl)-3-phenylisoxazol-4-yl)benzenesulfonamide (1.11 g,3.18 mmol, prepared according to the method of Talley, J. J., et. al. J.Med. Chem. 2000, 43, 775-777) in THF (20 mL). The resulting mixture washeated at reflux for 4 hours, then poured into ice containing aqueousNH₄Cl and extracted with EtOAc. The combined extracts were washed withwater, dried over Na₂SO₄, filtered, and concentrated. Flashchromatography (silica gel, 1:1 EtOAc:THF) of the residue afforded thetitle compound as a white solid, (1.08 g, yield 87% yield). ¹H NMR (300MHz, DMSO-d₆) δ 7.87 (d, J=8.3 Hz, 2H), 7.6-7.3 (m, 9H), 4.59 (s, 2H),4.43 (t, J=5.1 Hz, 1H, OH), 3.55 (t, J=6.4 Hz, 2H), 3.46 (m, 2H), 1.67(pentet, J=6.3 Hz, 2H). Mass spectrum (API-TIS) m/z 389 (MH⁺).

26b.4-(5-(3-Nitrooxy)propoxy)methyl)-3-phenylisoxazol-4-yl)benzenesulfonamide

HNO₃ (90%, 1 mL) was added to Ac₂O (6 mL) at −10° C. (ice-MeOH bath),and the solution was stirred at the same temperature for 30 min. Theproduct of Example 26a (910 mg, 2.34 mmol) in THF (10 mL) was added, andthe resulting solution was stirred at −10° C. for 20 min. The mixturewas then poured into ice containing aqueous Na₂CO₃ and extracted withEtOAc. The combined extracts were washed with brine, dried over Na₂SO₄,filtered, and concentrated. Flash chromatography (silica gel, 2:1EtOAc:Hexane) gave the title compound as a white solid (0.9 g, 86%yield), ¹H NMR (300 MHz, DMSO-d₆) δ 7.87 (d, J=6.1 Hz, 2H), 7.5-7.3 (m,9H), 4.63 (s, 2H), 4.56 (t, J=6.4 Hz, 2H), 3.58 (t, J=6.1 Hz, 2H), 1.94(pentet, J=6.2 Hz, 2H). Mass spectrum (API-TIS) m/z 434 (MH⁺).

Example 274-(5-(2-Nitrooxy)ethoxy)methyl)-3-phenylisoxazol-4-yl)benzene-sulfonamide27a.4-(5-(2-Hydroxyethoxy)methyl)-3-phenylisoxazol-4-yl)benzenesulfonamide

Sodium (0.828 g, 36 mmol) was dissolved in ethylene glycol (15 mL) andto this was added a solution of4-(5-(chloromethyl)-3-phenylisoxazol-4-yl)benzenesulfonamide (1.80 g,5.17 mmol, prepared according to the procedure of Talley, J. J., et. al.J. Med. Chem. 2000, 43, 775-777.)) in THF (15 mL). The resulting mixturewas heated at reflux for 4 hours, then poured into ice containingaqueous NH₄Cl, extracted with EtOAc. The combined extracts were washedwith water, dried over Na₂SO₄, filtered, and concentrated. Flashchromatography (silica gel, 1:1 EtOAc:THF) of the residue afforded thetitle compound as a white solid (1.65 g, 85% yield). ¹H NMR (300 MHz,CDCl₃) δ 7.88 (d, J=8.5 Hz, 2H), 7.38-7.27 (m, 7H), 5.53 (br, 2H), 4.59(s, 2H), 3.70 (t, J=3.8 Hz, 2H), 3.63 (t, J=3.8 Hz, 2H), 2.63 (br, 1H).Mass spectrum (API-TIS) m/z 375 (MH⁺).

27b.4-(5-(2-Nitrooxy)ethoxy)methyl-3-phenylisoxazol-4-yl)benzenesulfonamide

Fuming HNO₃ (90%, 1 mL) was added to Ac₂O (6 mL) at −10° C. (ice-MeOHbath), and the solution was stirred at the same temperature for 30 min.The product of Example 27a (1.00 g mg, 2.67 mmol) in THF (10 mL) wasadded, and the resulting solution was stirred at −10° C. for 20 min. Themixture was then poured into ice containing aqueous Na₂CO₃ and extractedwith EtOAc. The combined extracts were washed with brine, dried overNa₂SO₄, filtered, and concentrated. Flash chromatography (silica gel,2:1 EtOAc:Hexane) gave the title compound as a white solid (0.81 g, 72%yield). ¹H NMR (300 MHz, CDCl₃) δ 7.89 (d, J=8.4 Hz, 2H), 7.38-7.30 (m,7H), 5.46 (br, 2H), 4.60 (t, J=3.0 Hz, 2H), 4.58 (s, 2H), 3.83 (t, J=3.0Hz, 2H). ¹³C NMR (75 MHz, CDCl₃) δ 165.5, 161.2, 141.7, 133.6, 130.3,129.9, 128.4, 127.7, 126.7, 117.4, 71.7, 66.9, 62.3. Mass spectrum(API-TIS) m/z 420 (MH⁺).

Example 284-(5-(4-Chlorophenyl)-3-((3-(nitrooxy)propoxy)methyl)pyrazolyl)benzenesulfonamide28a.4-(5-(4-Chlorophenyl)-3-((3-hydroxypropoxy)methyl)pyrazolyl)benzenesulfonamide

The title compound was prepared using the procedure of Example 20f. ¹HNMR (300 MHz, CDCl₃) δ 7.76 (d, J=8.5 Hz, 2H), 7.31-7.25 (m, 4H), 7.11(d, J=8.5 Hz, 2H), 6.51 (s, 1H), 6.07 (br, 2H), 4.58 (s, 2H), 3.8-3.7(m, 4H), 3.1 (br, 1H), 1.9-1.8 (m, 2H). Mass spectrum (API-TIS) m/z 421(MH⁺).

28b.4-(5-(4-Chlorophenyl)-3-((3-(nitrooxy)propoxy)methyl)pyrazolyl)benzenesulfonamide

The title compound was prepared from the product of Example 28a usingthe procedure of Example 20g. ¹H NMR (300 MHz, CDCl₃) δ 7.80 (d, J=8.4Hz, 2H), 7.34-7.29 (m, 4H), 7.14 (d, J=8.4 Hz, 2H), 6.55 (s, 1H), 5.67(br, 2H), 4.62-4.57 (m, 4H), 3.7-3.6 (m, 2H), 2.1-2.0 (m, 2H).). Massspectrum (API-TIS) m/z 467 (MH⁺).

Example 294-(3-((3-(Nitrooxy)propoxy)methyl)-5-phenylpyrazolyl)benzenesulfonamide29a 4-(3-((3-Hydroxypropoxy)methyl)-5-phenylpyrazolyl)benzenesulfonamide

The title compound was prepared using the procedure of Example 20f. ¹HNMR (300 MHz, CDCl₃) δ 7.74 (d, J=8.8 Hz, 2H), 7.33-7.27 (m, 5H), 7.171(d, J=8.8 Hz, 2H), 6.52 (s, 1H), 5.95 (br, 2H), 4.62 (s, 2H), 3.8-3.7(m, 4H), 3.2 (br, 1H), 1.9-1.8 (m, 2H). Mass spectrum (API-TIS) m/z 387(MH⁺).

29b.4-(3-((3-(Nitrooxy)propoxy)methyl)-5-phenylpyrazolyl)benzenesulfonamide

The title compound was prepared from the product of Example 29a usingthe procedure of Example 20g. ¹H NMR (300 MHz, CDCl₃) δ 7.82-7.79 (m,2H), 7.40-7.33 (m, 5H), 7.23-7.20 (m, 2H), 6.55 (s, 1H), 5.23 (br, 2H),4.63-4.58 (m, 4H), 3.7-3.6 (m, 2H), 2.1-2.0 (m, 2H). Mass spectrum(API-TIS) m/z 432 (MH⁺).

Example 304-(1-Cyclohexyl-3-(2-(nitrooxy)ethyl)pyrazol-5-yl)-1-(methylsulfonyl)benzene30a. 4-(1-Cyclohexyl-3-vinylpyrazol-5-yl)-1-methylthiobenzene

A solution of BuLi (5.07 mL of 1.6 M solution in hexane, 8.1 mmol) wasadded to a stirred solution of methyltriphenylphosphoniumbromide (2.3 g,6.5 mmol) in THF (20 mL) at −78° C. under N2. The resulting solution wasstirred for 30 minutes and then a solution of the product of Example 4c(1.3 g, 4.3 mmol) in THF (10 mL) was added. The cold bath was removedand the mixture was stirred at room temperature for 2 hours. SaturatedNH₄Cl (50 mL) was added and the mixture was extracted with EtOAc. Thecombined organic extracts were dried over Na₂SO₄. The solvent wasevaporated and crude product was chromatographed on silica gel elutingwith (0.5:10) EtOAC:Hexane to give the title compound (0.92 g, 71%yield) as an oil. ¹H NMR (300 MHz, CDCl₃) δ 7.21 (d, J=8.4 Hz, 2H), 7.16(d, J=8.3 Hz, 2H), 6.68 (dd, J=11 and 17.7 Hz, 1H), 6.25 (s, 1H), 5.58(d, J=17.7 Hz, 1H), 5.16 (d, J=11 Hz, 1H), 3.85-3.96 (m, 1H), 2.42 (s,3H), 1.50-2.00 (m, 7H), 1.05-1.20 (m, 3H); ¹³C NMR (75 MHz, CDCl₃) δ149.7, 143.1, 139.2, 129.5, 129.2, 127.4, 126.2, 114.4, 102.1, 57.6,33.2, 25.5, 25.0, 15.3. Mass spectrum (API-TIS) m/z 299 (MH⁺). Anal.Calcd. for C₁₈H₂₂N₂O₂S.¼ mol H₂O: C, 64.54; H, 6.77; N, 8.36. Found: C,64.26; H, 6.45; N, 8.32.

30b. 2-(1-Cyclohexyl-5-(4-methylthiophenyl)pyrazol-3-yl)-1-ethan-1-ol

A solution of 1M BH₃.THF complex (6 mL, 6 mmol) was added drop-wise to astirred solution of product of Example 30a (0.9 g, 3 mmol) in THF at 0°C. and stirred for 45 minutes at 0° C. 10% NaOH (6 mL) followed by 30%H₂O₂ solution (6 mL) were added drop-wise. The product was extractedwith EtOAc, dried over Na₂SO₄ and concentrated under reduced pressure.The crude material was chromatographed on silica gel eluting with (1:1)EtOAc:Hexane to give the title compound (0.18 g, 19% yield) as an oil.¹H NMR (300 MHz, CDCl₃) δ 7.23 (d, J=8.3 Hz, 2H), 7.17 (d, J=8.3 Hz,2H), 5.95 (s, 1H), 3.82-3.96 (m, 1H), 3.84 (t, J=5.7 Hz, 2H), 3.30 (brs, 1H), 2.80 (t, J=5.7 Hz, 2H), 2.44 (s, 3H), 1.05-1.95 (m, 10H); ¹³CNMR (75 MHz, CDCl₃) δ 149.5, 142.8, 139.2, 129.2, 127.5, 126.2, 104.7,61.9, 57.5, 33.3, 30.9, 25.6, 25.1, 15.4. Mass spectrum (API-TIS) m/z317 (MH⁺).

30c.2-(1-Cyclohexyl-3-(2-hydroxyethyl)pyrazol-5-yl)-1-(methylsulfonyl)benzene

The title compound (0.18 g, 96% yield) was prepared from the product ofExample 30b (0.17 g, 0.53 mmol) and OXONE® (0.66 g, 1.07 mmol) using theprocedure for Example 1g. Mp 108° C. ¹H NMR (300 MHz, CDCl₃) δ 7.95 (d,J=8.1 Hz, 2H), 7.48 (d, J=8.1 Hz, 2H), 6.07 (s, 1H), 3.81-3.94 (m, 1H),3.83 (t, J=5.9 Hz, 2H), 3.33 (br s, 1H), 3.05 (s, 3H), 2.81 (t, J=5.9Hz, 2H), 1.50-2.05 (m, 7H), 1.05-1.25 (m, 3H); ¹³C NMR (75 MHz, CDCl₃)149.8, 141.2, 140.1, 136.4, 129.5, 127.7, 105.6, 61.7, 57.9, 44.3, 33.2,30.9, 25.4, 24.9. Mass spectrum (API-TIS) m/z 349 (MH⁺).

30d.4-(1-Cyclohexyl-3-(2-(nitrooxy)ethyl)pyrazol-5-yl)-1-(methylsulfonyl)benzene

The title compound (0.12 g, 66% yield) was prepared from the product ofExample 30c (0.16 g, 0.45 mmol), fuming HNO₃ (94 μL, 0.14 g, 2.24 mmol)and Ac₂O (0.34 mL, 0.37 g, 3.58 mmol) using the procedure for Example1h. Mp 117° C. ¹H NMR (300 MHz, CDCl₃) δ 7.98 (d, J=8.3 Hz, 2H), 7.50(d, J=8.3 Hz, 2H), 6.15 (s, 1H), 4.70 (t, J=6.7 Hz, 2H), 3.85-4.05 (m,1H), 3.07 (s, 3H), 3.04-3.08 (m, 2H), 1.60-2.00 (m, 7H), 1.10-1.30 (m,3H); ¹³C NMR (75 MHz, CDCl₃) δ 146.5, 141.9, 140.6, 135.9, 129.7, 127.8,106.0, 71.9, 58.4, 44.3, 33.1, 26.0, 25.5, 24.8. Mass spectrum (API-TIS)m/z 394 (MH⁺).

Example 314-(1-Cyclohexyl-3-(3-(nitrooxy)propyl)pyrazol-5-yl)-1-(methylsulfonyl)benzene31a. Methyl(2E)-3-(1-cyclohexyl-5-(4-methylthiophenyl)pyrazol-3-yl)prop-2-enoate

A solution of BuLi (3.2 mL of 1.6 M solution in hexane, 5.2 mmol) wasadded to a stirred solution of trimethylphosphonoacetate (0.92 g, 5.08mmol) in THF (10 mL) at −78° C. under N₂. The resulting solution wasstirred for 30 minutes and a solution of the product of Example 4c (1.22g, 4.06 mmol) in THF (10 mL) was added. The cold bath was removed andthe mixture was stirred at room temperature for 2 hours. Water (50 mL)was added and the mixture was extracted with EtOAc. The combined organicextracts were dried over Na₂SO₄. The solvent was evaporated and crudeproduct was chromatographed on silica gel eluting with (1:9)EtOAc:Hexane to give the title compound (1.12 g, 77% yield) as an oil.¹H NMR (300 MHz, CDCl₃) δ 7.71 (d, J=16 Hz, 1H), 7.32 (d, J=6.5 Hz, 2H),7.23 (d, J=6.8 Hz, 2H), 6.43 (s, 1H), 6.38 (d, J=16 Hz, 1H), 4.03-4.08(m, 1H), 3.93 (s, 3H), 2.52 (s, 3H), 1.55-2.00 (m, 7H), 1.22-1.28 (m,3H); ¹³C NMR (75 MHz, CDCl₃) δ 167.4, 146.8, 143.7, 139.8, 137.4, 129.3,126.7, 126.2, 118.0, 104.6, 58.1, 51.4, 33.2, 25.5, 25.0, 15.3. Massspectrum (API-TIS) m/z 357 (MH⁺).

31b.(2E)-3-(1-Cyclohexyl-5-(4-methylthiophenyl)pyrazol-3-yl)prop-2-en-1-ol

The title compound (0.62 g, 60% yield) was prepared from the product ofExample 31a (1.12 g, 3.4 mmol) and lithium aluminum hydride (3.4 mL of1M solution in THF, 0.13 g, 3.4 mmol) using the procedure for Example1f. Mp 90° C. ¹H NMR (300 MHz, CDCl₃) δ 7.25-7.35 (m, 4H), 6.68 (d, J=16Hz, 1H), 6.32-6.39 (m, 1H), 6.31 (s, 1H), 4.30 (d, J=5.5 Hz, 2H),3.98-4.06 (m, 1H), 2.53 (s, 3H), 1.60-1.95 (m, 7H), 1.10-1.30 (m, 3H);¹³C NMR (75 MHz, CDCl₃) δ 148.8, 143.3, 139.4, 129.6 129.3, 127.5,123.9, 102.6, 63.6, 57.7, 33.3, 25.6, 25.1, 15.4. Mass spectrum(API-TIS) m/z 329 (MH⁺).

31c. 4-(3-((1E)-3-Hydroxyprop-1-enyl)-1-cyclohexylpyrazol-5-yl)-1(methylsulfonyl)benzene

The title compound (0.52 g, 76% yield) was prepared from the product ofExample 31b (0.62 g, 1.89 mmol) and OXONE® (1.45 g, 2.36 mmol) using theprocedure for Example 1g. Mp 121° C. ¹H NMR (300 MHz, CDCl₃) δ 7.99 (d,J=8.4 Hz, 2H), 7.52 (d, J=8.4 Hz, 2H), 6.49 (d, J=16 Hz, 1H), 6.35 (s,1H), 6.29-6.38 (m, 1H), 4.27 (d, J=5.5 Hz, 2H), 3.90-3.98 (m, 1H), 3.09(s, 3H), 1.60-2.10 (m, 7H), 1.10-1.30 (m, 3H); ¹³C NMR (75 MHz, CDCl₃) δ149.1, 141.7, 140.4, 136.4, 130.3, 129.7, 127.8, 123.2, 103.6, 63.4,58.2, 44.4, 33.3, 25.5, 24.9. Mass spectrum (API-TIS) m/z 361 (MH⁺).

31d.4-(1-Cyclohexyl-3-(3-hydroxypropyl)pyrazol-5-yl)-1-(methylsulfonyl)benzene

The product of Example 31c (0.52 g, 1.44 mmol) was dissolved in EtOH (20mL) and degassed with N₂.10% Pd/C (2 spatula) was added and hydrogenated(20 p.s.i.) for 3 hours. The carbon residue was removed by filtrationand the solvent was removed under reduced pressure. The crude materialwas chromatographed on silica gel eluting with (2:1) EtOAc:Hexane togive the title compound (0.37 g, 71% yield) as a white solid. Mp 138° C.¹H NMR (300 MHz, CDCl₃) δ 8.03 (d, J=8.2 Hz, 2H), 7.54 (d, J=8.1 Hz,2H), 6.11 (s, 1H), 3.90-4.00 (m, 1H), 3.75 (t, J=5.8 Hz, 2H), 3.30 (brs, 1H), 3.13 (s, 3H), 2.81 (t, J=6.9 Hz, 2H), 1.60-2.10 (m, 9H),1.15-1.30 (m, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 151.7, 141.4, 140.2, 136.6,129.6, 127.8, 105.5, 62.7, 58.0, 44.4, 33.4, 31.5, 25.5, 24.9. Massspectrum (API-TIS) m/z 363 (MH⁺).

31e.4-(1-Cyclohexyl-3-(3-(nitrooxy)propyl)pyrazol-5-yl)-1-(methylsulfonyl)benzene

The title compound (0.11 g, 70% yield) was prepared from the product ofExample 31d (0.14 g, 0.38 mmol), fuming HNO₃ (81 μL, 0.12 g, 1.93 mmol)and Ac₂O (0.29 mL, 0.31 g, 3.09 mmol) by following the procedure for theExample 1h. Mp 77° C. ¹H NMR (300 MHz, CDCl₃) δ 8.04 (d, J=8.1 Hz, 2H),7.55 (d, J=8.1 Hz, 2H), 6.19 (s, 1H), 4.53 (t, J=6.4 Hz, 2H), 3.95-4.07(m, 1H), 3.11 (s, 3H), 2.85 (t, J=7.45 Hz, 2H), 1.69-2.20 (m, 9H),1.10-1.30 (m, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 150.1, 142.5, 140.9, 135.2,129.7, 127.9, 105.7, 72.4, 58.8, 44.3, 32.8, 26.4, 25.4, 24.6, 23.7.Mass spectrum (API-TIS) m/z 408 (MH⁺).

Example 324-(5-((2,2-Difluoro-3-(nitrooxy)propoxy)methyl)-3-phenylisoxazol-4-yl)benzenesulfoamide32a. 2,2-Difluoropropane-1,3-diol

To a stirred solution of diethyldifluoromalonate (5.00 g, 25.5 mmol) inTHF (100 mL) at 0° C. was added lithium aluminum hydride (1.0 M in THF,61 mL, 61 mmol) drop-wise under nitrogen atmosphere. The reactionmixture was stirred for 3 hours, and then cautiously quenched by solidsodium sulfate decahydrate (15 g). The resulting mixture was aged for 30minutes, filtered, and the filter cake was thoroughly rinsed with 1:1mixture of methanol and THF. The combined filtrates were dried overmagnesium sulfate, filtered, and concentrated to give the title compound(1.58 g, 55% yield) as a white solid which required no furtherpurification (the yield can be improved up to 82% when the reaction wasperformed at −78° C.): ¹H NMR (300 MHz, DMSO-d₆) δ 5.41 (br, 2H), 3.66(t, J(¹⁹F, ¹H)=13.8 Hz, 4H); ¹³C NMR (75 MHz, DMSO-d₆) δ 123.7 (t,J(¹⁹F, ¹³C)=242 Hz), 60.9 (t, J(¹⁹F, ¹³C)=29.4 Hz); LRMS (API-TIS) m/z113.2 ((M+H)⁺).

32b. 4-(5-(Chloromethyl)-3-phenylisoxazol-4-yl)benzenesulfonamide

This compound was prepared according to the method of Talley, J. J. etal. J. Med. Chem. 43, 775-777, 2000.

32c.4-(5-((2,2-Difluoro-3-hydroxypropoxy)methyl)-3-phenylisoxazol-4-yl)benzenesulfonamide

To a stirred solution of the product of Example 32a (3.37 g, 30 mmol) inTHF (100 mL) was added NaH (0.72 g, 30 mmol) portionwise. The mixturewas stirred at ambient temperature until gas evolution was no longerobserved (ca. 15 min). The product of Example 32b (2.09 g, 6.00 mmol) inTHF (20 mL) was added, and the reaction mixture was heated at reflux for35 minutes, at which point the starting chloride was completely consumedas indicated by TLC. Upon cooling, the mixture was poured into aqueousammonium chloride, extracted with ethyl acetate (2×). The combinedorganic layers were washed with water (3×), dried over sodium sulfate,filtered, and concentrated. Chromatography of the residue (silica gel,5% methanol in dichloromethane) gave the title compound (1.96 g, 77%yield) as a beige solid. Mp 93-94° C. ¹H NMR (300 MHz, DMSO-d₆) δ 7.91(d, J=8.5 Hz, 2H), 7.52-7.40 (m, 9H), 5.64 (t, J=6.2 Hz, 1H), 4.78 (s,2H), 3.89 (t, J(¹⁹F, ¹H)=13.5 Hz, 2H), 3.68 (td, J(¹⁹F, ¹H)=13.8 Hz,J(1H, ¹H)=6.2 Hz, 2H). LRMS (API-TIS) m/z 425.2 ((M+H)⁺).

32d.4-(5-((2,2-Difluoro-3-(nitrooxy)propoxy)methyl)-3-phenylisoxazol-4-yl)benzenesulfoamide

Nitric acid (90%, 1.41 mL, 30 mmol, 20 equiv.) was added to stirredacetic anhydride (4.3 mL) at 0° C. After 15 minutes, a pre-cooled (0°C.) solution of the product of Example 32c (0.637 g, 1.50 mmol) in THF(5 mL) was added, and the reaction mixture was stirred at the sametemperature for 45 minutes. TLC indicated complete conversion of thestarting alcohol. The mixture was diluted with ethyl acetate, washedwith ice-cooled 2M aqueous sodium carbonate (2 x), and water. Theorganic layer was dried over sodium sulfate, filtered, and concentrated.The resulting semisolid was purified by crystallization fromdichloromethane/hexanes (1:1) to give the title compound (0.605 g, 86%yield) as white needles. Mp 69° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.94 (d,J=8.5 Hz, 2H), 7.42-7.35 (m, 7H), 5.11 (br, 2H), 4.77 (t, J (¹⁹F,¹H)=11.9 Hz, 2H), 4.69 (s, 2H), 3.87 (t, J(¹⁹F, ¹H)=12.0 Hz, 2H); LRMS(API-TIS) m/z 470.0 ((M+H)⁺).

Example 334-(3-Phenyl-5-((2,2,3,3-tetrafluoro-4-(nitrooxy)butoxy)methyl)isoxazol-4-yl)benzenesulfonamide33a.4-(3-Phenyl-5-(2,2,3,3-tetrafluoro-4-hydroxy)methyl)isoxazol-4-yl)benzenesulfonamide

To a stirred solution of 2,2,3,3-tetrafluorobutane-1,4-diol (5.78 g,35.7 mmol) in THF (150 mL) was added NaH (0.857 g, 35.7 mmol)portionwise at room temperature. After 15 minutes, the product ofExample 32b (2.49 g, 7.14 mmol) in THF (20 mL) was added, and thereaction mixture was heated at reflux under nitrogen atmosphere for 55minutes, at which point the starting chloride was no longer observableby TLC. Upon cooling, the mixture was diluted with ethyl acetate, washedwith aqueous ammonium chloride, water, and brine. The organic layer wasdried over sodium sulfate, filtered, and concentrated. Crystallizationof the residue from ethyl acetate gave the title compound (2.66 g, 79%yield) as white flakes. Mp 70° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 7.86 (d,J=8.3 Hz, 2H), 7.53-7.36 (m, 9H), 5.88 (t, J=4.8 Hz, 1H), 4.79 (s, 2H),4.12 (t, J (¹⁹F, ¹H)=15.5 Hz, 2H), 3.81 (td, J (¹⁹F, ¹H)=15.2 Hz, J (¹H,¹H)=4.8 Hz, 2H); LRMS (API-TIS) m/z 475.2 ((M+H)⁺).

33b.4-(3-Phenyl-5-(2,2,3,3-tetrafluoro-4-hydroxy)methyl)isoxazol-4-yl)benzenesulfonamide

Nitric acid (90%, 4.66 mL, 100 mmol, 18 equiv.) was added to stirredacetic anhydride (14 mL) at 0° C. After 15 min, a pre-cooled (0° C.)solution of the product of Example 33a (2.66 g, 5.60 mmol) in THF (30mL) was added, and the reaction mixture was stirred under ambientatmosphere for 75 minutes. TLC indicated complete conversion of thestarting alcohol. The mixture was diluted with ethyl acetate, washedwith ice plus 2M aqueous sodium carbonate (2×), and water. The organiclayer was dried over sodium sulfate, filtered, and concentrated. Theresulting solid was purified by crystallization fromdichloromethane/hexanes (1:1) to furnish the title compound (2.36 g, 81%yield) as white prisms. Mp 46° C. ¹H NMR (300 MHz, CDCl₃) δ 7.92 (d,J=8.5 Hz, 2H), 7.41-7.33 (m, 7H), 5.37 (br, 2H), 4.95 (t, J(¹⁹F,¹H)=13.7 Hz, 2H), 4.71 (s, 2H), 4.05 (t, J(¹⁹F, ¹H)=13.2 Hz, 2H). LRMS(API-TIS) m/z 520.2 ((M+H)⁺).

Example 344-(5-((2,2,3,3,4,4-Hexafluoro-5-(nitrooxy)pentyloxy)methyl)-3-phenylisoxazol-4-yl)benzenesulfonamide34a.4-(5-((2,2,3,3,4,4-Hexafluoro-5-hydroxypentyloxy)methyl)-3-phenylisoxazol-4-yl)benzenesulfonamide

To a stirred solution of 2,2,3,3,4,4-hexafluoropentane-1,5-diol (6.36 g,30 mmol) in THF (100 mL) was added sodium hydride (0.72 g, 30 mmol) insmall portions. The mixture was stirred at ambient temperature untilhydrogen evolution had ceased (ca. 10 min). The product of Example 32b(2.12 g, 6.09 mmol) in THF (25 mL) was added, and the reaction mixturewas heated at reflux under nitrogen atmosphere for 80 minutes, at whichpoint the starting chloride was completely converted as judged by TLC.The mixture was poured into ice plus aqueous ammonium chloride withswirling, and extracted with ethyl acetate (2×). The combined organicextracts were washed with water, dried over sodium sulfate, filtered,and concentrated. Chromatography of the residue (silica gel, 5% ethanolin ethyl acetate) afforded the title compound (2.62 g, 82% yield) as awhite crystalline solid. Mp 50-51° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 7.90(d, J=8.3 Hz, 2H), 7.57-7.41 (m, 9H), 6.00 (t, J=5.6 Hz, 1H), 4.86 (s,2H), 4.27 (t, J(¹⁹F, ¹H)=15.2 Hz, 2H), 3.97 (td, J(¹⁹F, ¹H)=15.7 Hz,J(1H, ¹H)=5.6 Hz, 2H); LRMS (API-TIS) m/z 525.2 ((M+H)⁺).

34b.4-(5-((2,2,3,3,4,4-Hexafluoro-5-(nitrooxy)pentyloxy)methyl)-3-phenylisoxazol-4-yl)benzenesulfonamide

Nitric acid (90%, 4.19 mL, 90 mmol, 30 equiv.) was added to stirredacetic anhydride (12.6 mL) at 0° C. After 15 min, a pre-cooled (0° C.)solution of the product of Example 34a (1.58 g, 3.01 mmol) in THF (20mL) was added, and the reaction mixture was stirred at 0° C. underambient atmosphere for 105 minutes. TLC indicated complete conversion ofthe starting alcohol. The mixture was diluted with ethyl acetate, washedwith ice water plus 2M aqueous sodium carbonate (2×), and water. Theorganic layer was dried over sodium sulfate, filtered, and concentrated.The resulting oil was purified by crystallization twice fromdichloromethane/hexanes (1:1) to give the title compound (1.25 g, 73%yield) as a white solid. Mp 38-39° C. ¹H NMR (300 MHz, CDCl₃) δ 7.93(dd, J=6.9, 1.7 Hz, 2H), 7.45-7.33 (m, 7H), 5.23 (br, 2H), 4.99 (t,J(¹⁹F, ¹H)=13.5 Hz, 2H), 4.72 (s, 2H), 4.10 (t, J(¹⁹F, ¹H)=13.7 Hz, 2H).LRMS (API-TIS) m/z 570.2 ((M+H)⁺).

Example 351-(5-(4-(Methylsulfonyl)phenyl)-1-(2-pyridyl)pyrazol-3-yl)-2-(nitrooxy)ethan-1-one35a.2-Bromo-1-(5-(4-methylthiophenyl)-1-(2-pyridyl)pyrazol-3-yl)ethan-1-one

To a stirred solution of methyl5-(4-methylthiophenyl)-1-(2-pyridyl)pyrazole-3-carboxylate (prepared asdescribed in Penning, T. D. et al. J. Med. Chem. 1997, 40, 1347-1365;0.39 g, 1.2 mmol) and dibromomethane (0.17 mL, 2.4 mmol) in THF (10 mL)at −78° C. under nitrogen atmosphere was added methyllithium (1.6 M inether, 1.4 mL, 2.2 mmol). After being stirred at the same temperaturefor 90 minutes, the solution was quenched with aqueous sodiumbicarbonate, and extracted with ethyl acetate. The combined organicextracts were dried over sodium sulfate, filtered, and concentrated.Chromatography of the residue on silica gel (2:1 EtOAc:hexane) gave thetitle compound (0.32 g, 69% yield) as a white foam. ¹H NMR (300 MHz,CDCl₃) δ 8.42-8.40 (m, 1H), 7.83 (m, 1H), 7.55-7.51 (m, 1H), 7.17-7.09(m, 4H), 7.02 (s, 1H), 4.70 (s, 2H), 2.46 (s, 3H); LRMS (API-TIS) m/z388 and 390 (MH⁺).

35b. 2-Bromo-1-(5-(4-(methylsulfonyl)pyrazol-3-yl)ethan-1-one

To a stirred solution of the product of Example 35a (0.32 g, 0.823 mmol)in methanol (15 mL) was added OZONE® (1.01 g, 1.65 mmol) in water (10mL). After being stirred at ambient temperature for 30 minutes, themixture was extracted with ethyl acetate, dried over sodium sulfate,filtered, and concentrated. Chromatography of the residue on silica gel(2:1 EtOAc:hexane) gave the title compound (0.34 g) as a white solid. Mp116° C. ¹H NMR (300 MHz, CDCl₃) δ 8.32-8.30 (m, 1H), 7.95-7.91 (m, 3H),7.79-7.76 (m, 1H), 7.50-7.36 (m, 3H), 7.14 (s, 1H), 4.70 (s, 2H), 3.10(s, 3H). LRMS (API-TIS) m/z 420 and 422 (MH⁺).

35c.1-(5-(4-(Methylsulfonyl)phenyl)-1-(2-pyridyl)pyrazol-3-yl)-2-(nitrooxy)ethan-1-one

To a stirred solution of the product of Example 35b (0.21 g, 0.499 mmol)in acetonitrile (10 mL) was added silver nitrate (0.425 g, 2.5 mmol).After being stirred at ambient temperature for 20 hours, the mixture wasconcentrated and chromatographed on silica gel (1:1 EtOAc:hexane) togive the title compound (0.19 g) as a white solid. Mp 82-84° C. ¹H NMR(300 MHz, CDCl₃) δ 8.34-8.33 (m, 1H), 7.95-7.91 (m, 3H), 7.75-7.72 (m,1H), 7.50-7.22 (m, 3H), 7.15 (s, 1H), 5.78 (s, 2H), 3.10 (s, 3H). LRMS(API-TIS) m/z 403.2 (MH⁺).

Example 364-(5-(Chlorophenyl)-3-((3-(nitrooxy)propoxy)methyl)benzene-sulfonamide36a. 5-(4-Chlorophenyl)-1-(4-sulfamoylphenyl)pyrazol-3-yl)methylmethylsulfonate

To a stirred solution of4-(5-(4-chlorophenyl)-3-(hydroxymethyl)pyrazoyl)-benzenesulfonamide(prepared as described in Penning, T. D. et al. J. Med. Chem. 1997, 40,1347-1365; 8.50 g, 23.2 mmol) in THF (200 mL) were added MeSO₂Cl (1.80mL, 232 mmol), di-isopropylethylamine (4.36 mL, 25 mmol). After beingstirred at room temperature for 90 minutes, the mixture wasconcentrated, poured into 2 N HCl, and extracted with ethyl acetate. Theorganic layer was dried over sodium sulfate, filtered, and concentratedto give the title compound (10 g) as a white foam, which was usedwithout further purification.

36b.4-(5-(4-Chlorophenyl)-3-((3-hydroxypropoxy)methyl)pyrazolyl)-benzenesulfonamide

Sodium (0.69 g, 30 mmol) was dissolved in 1,3-dihydroxypropane (15 mL).The product of Example 36b (4.21 g, 10 mml) in THF (50 mL) was added,and the mixture was heated at reflux for 5 hours, and then poured intoice plus aqueous ammonium chloride. The mixture was extracted with ethylacetate, washed with brine, dried over sodium sulfate, filtered, andconcentrated. The resulting solid was purified by crystallization from1:5 MeOH:CHCl₃ to give the title compound (2.12 g) as white needles. Mp96° C. ¹H NMR (300 MHz, CDCl₃) δ 7.77 (d, J=8.7 Hz, 2H), 7.31-7.25 (m,4H), 7.13-7.09 (m, 2H), 6.51 (s, 1H), 6.07 (br, 2H), 4.58 (s, 2H),3.75-3.70 (m, 4H), 3.18 (br, 1H), 1.85-1.80 (m, 2H). LRMS (API-TIS) m/z422.2 (MH⁺).

36c.4-(5-(Chlorophenyl)-3-((3-(nitrooxy)propoxy)methyl)benzene-sulfonamide

Nitric acid (90%, 1.2 mL, 25 mmol) and acetic anhydride (3.6 mL) weremixed and stirred at 0° C. for 15 min, the product of Example 36b (1.23g, 2.92 mmol) in THF (10 mL) was then added. After being stirred at 0°C. for 20 minutes, the mixture was poured into ice plus 2M sodiumcarbonate, extracted with ethyl acetate, washed with brine, dried oversodium sulfate, filtered, and concentrated. The residue was purified bycrystallization from 1:1 dichloromethane:hexanes to give the titlecompound (1.11 g) as a yellow solid. Mp 88° C. ¹H NMR (300 MHz, CDCl₃) δ7.80 (d, J=8.6 Hz, 2H), 7.34-7.29 (m, 4H), 7.14 (d, J=8.6 Hz, 2H), 6.55(s, 1H), 5.67 (br s, 2H), 4.61-4.57 (m, 4H), 3.68 (t, J=5.9 Hz, 2H),2.04 (m, 2H). LRMS (API-TIS) m/z 467 (MH⁺).

Example 374-(5-((2-(Nitrooxy)ethyl)sulfonyl)ethoxy)methyl)-3-phenylisoxazol-4-yl)benzenesulfonamide37a.4-(5-((2-(2-Hydroxyethylthio)ethoxy)methyl)-3-phenylisoxazol-4-yl)benzenesulfonamide

Sodium (0.69 g, 30 mmol) was dissolved in 2,2′-thiodiethanol (10 mL) at50° C. 4-((5-Chloromethyl-3-phenyl)-4-isoxazolyl)benzenesulfonamide(synthesized as described in Talley et al.; J. Med. Chem. 2002, 43,775-777; 1.19 g, 3.41 mmol) in THF (25 mL) was added, and the solutionwas heated at reflux under nitrogen atmosphere for 150 minutes. Themixture was poured into aqueous ammonium chloride, extracted with EtOAc,washed with water, dried over sodium sulfate, filtered, and concentratedto give an oil (2.38 g), which was used without further purification.

37b.4-(5-((2-((2-Hydroxyethyl)sulfonyl)ethoxy)methyl)-3-phenylisoxazol-4-yl)benzenesulfonamide

To a stirred solution of the product of Example 37a (2.38 g crude) inmethanol (150 mL) was added OXONE® (16.4 g, 26.6 mmol) in water (150mL). After being stirred at room temperature for 95 minutes, the mixturewas poured into water, and extracted with ethyl acetate. The combinedorganic extracts were washed with water, dried over sodium sulfate,filtered, and concentrated. Chromatography of the residue on silica gel(EtOAc) gave the title compound (1.28 g), as a white solid. Mp 81° C. ¹HNMR (300 MHz, THF-d₈) δ 7.97 (d, J=8.6 Hz, 2H), 7.7-7.4 (m, 7H), 6.22(br, 2H), 4.75 (s, 2H), 4.03-3.88 (m, 4H), 3.49-3.40 (m, 2H), 3.19-3.08(m, 2H), 3.03 (br, 1H). LRMS (API-TIS) m/z 467.2 (MH⁺).

37c.4-(5-((2-(Nitrooxy)ethyl)sulfonyl)ethoxy)methyl)-3-phenylisoxazol-4-yl)benzenesulfonamide

Nitric acid (90%, 2.5 mL, 51 mmol) and acetic anhydride (8 mL) weremixed and stirred at 0° C. for 15 minutes, the product of Example 37b(1.08 g, 2.31 mmol) in THF (10 mL) was then added. After being stirredat 0° C. for 20 minutes, the mixture was poured into ice plus 2M sodiumcarbonate, extracted with ethyl acetate, washed with brine, dried oversodium sulfate, filtered, and concentrated. The residue was purified bycrystallization from 3:1 dichloromethane:hexanes to give the titlecompound (0.81 g) as a white solid. Mp 62-63° C. ¹H NMR (300 MHz,THF-d⁸) δ 7.77 (d, J=8.3 Hz, 2H), 7.32-7.19 (m, 7H), 6.47 (br, 2H), 4.74(t, J=5.9 Hz, 2H), 4.53 (s, 2H), 3.83 (t, J=6.0 Hz, 2H), 3.41 (t, J=5.8Hz, 2H), 3.25 (t, J=5.8 Hz, 2H). LRMS (API-TIS) m/z 467.2 (MH⁺). LRMS(API-TIS) m/z 512.2 (MH⁺).

Example 381-(1-Cyclohexyl-3-(((2-hydroxyethyl)amino)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene38a.1-(1-Cyclohexyl-3-(hydroxymethyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene

The product of Example 4b (1.64 g, 5.43 mmol) was dissolved in MeOH/H₂O(6 mL/1 mL) and OXONE®was added (6.67 g, 10.86 mmol) and the mixturestirred at room temperature overnight. The resulting solid was removedvia filtration and washed with CH₂Cl₂. The filtrate was collected anddiluted with additional CH₂Cl₂ (10 mL) and the organic layer separated,dried, and the solvent removed under reduced pressure to give the titlecompound as a yellow solid (1.55 g, 86% yield). ¹H NMR (300 MHz, CDCl₃)δ 8.04 (d, 2H, J=8.3), 7.55 (d, 2H, J=8.3), 6.31 (s, 1H), 4.73 (s, 2H),3.99 (m, 1H), 3.12 (s, 3H), 2.04-2.02 (m, 2H), 1.89-1.86 (m, 4H), 1.66(m, 2H), 1.27-1.25 (m, 2H). Mass spectrum (API-TIS) m/z 335 (M+1).

38b.1-(3-(Bromomethyl)-1-cyclohexylpyrazol-5-yl)-4-(methylsulfonyl)benzene

The product of Example 38a (1.5o g, 4.49 mmol) was dissolved in CH₂Cl₂(10 mL) and PBr₃ (853.1 mg, 8.98 mmol) was added. The mixture wasstirred overnight at room temperature. Water (10 mL) was slowly addedand the organics separated, washed with brine, and dried (MgSO₄). Thesolvent was removed under reduced pressure to give of the title compoundas a white solid (1.29 g, 72% yield). ¹H NMR (300 MHz, CDCl₃) δ 8.03 (d,2H, J=7.4), 7.55 (d, 2H, J=7.4), 6.34 (s, 1H), 4.51 (s, 2H), 4.01-3.92(m, 1H), 3.11 (s, 3H), 2.02-1.98 (m, 2H), 1.88-1.85 (m, 4H), 1.64 (m,2H), 1.24 (m, 2H). Mass spectrum (API-TIS) m/z 398 (M+1).

38c.1-(1-Cyclohexyl-3-(((2-hydroxyethyl)amino)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene

The product of Example 38b (480 mg, 1.209 mmol) and ethanolamine (109.4uL, 1.813 mmol) were dissolved in acetonitrile (10 mL) and stirred atroom temperature for 48 hours. The acetonitrile was removed underreduced pressure and the resulting residue dissolved in CH₂Cl₂ (15 mL).The sample was washed with water (2×8 mL) and brine and dried (MgSO₄).The solvent was removed under reduced pressure to give of the titlecompound as a yellow oil (37 mg, 8% yield). ¹H NMR (300 MHz, CDCl₃) δ8.03 (d, 2H, J=8.3), 7.54 (d, 2H, J=8.3), 6.22 (s, 1H), 3.97 (brm, 1H),3.86 (s, 2H), 3.67 (t, 2H, J=5.1), 3.46 (s, 1H), 3.11 (s, 3H), 2.88 (t,2H, J=5.1), 2.04-2.01 (m, 2H), 1.88-1.85 (m, 4H), 1.65 (m, 2H),1.27-1.25 (m, 2H). Mass spectrum (API-TIS) m/z 378 (M+1).

Example 394-(1-(4-Methoxyphenyl)-3-((3-(nitrooxy)propoxy)methyl)pyrazol-5-yl)-1-(methylsulfonyl)benzene

Nitric acid (3 mL) was cooled to 0° C. and the product of Example 10d(31.2 mg, 0.075 mmol) in CH₃CN (2 mL) was added drop-wise. The mixturewas stirred at 0° C. for 6 hours and diluted with H₂O (3 mL). The samplewas neutralized with solid Na₂CO₃ and the aqueous portion extracted withCH₂Cl₂ (3×10 mL). The combined organic extracts were dried (MgSO₄),evaporated to give the title compound as a yellow oil (30.0 mg, 87%yield). ¹H NMR (300 MHz, CDCl₃) δ 7.84 (d, 2H, J=8.5), 7.40 (d, 2H,J=8.5), 7.17 (d, 2H, J=8.9), 6.87 (d, 2H, J=8.9) 6.60 (s, 1H), 4.61-4.56(m, 4H), 3.81 (s, 3H), 3.67 (t, 2H, J=6.1), 3.04 (s, 3H), 2.05-2.01 (t,2H, J=6.1). Mass spectrum (API-TIS) m/z 462 (M+1).

Example 404-(1-(4-Methyl-3-nitrophenyl)-3-((3-(nitrooxy)propoxy)methyl)pyrazol-5-yl)-1-(methylsulfonyl)benzene

The product of Example 8d (41.9 mg, 0.105 mmol) was cooled to 0° C. andcold HNO₃ (5 mL) was added drop-wise. The mixture was stirred at 0° C.for 2.5 hours and diluted with H₂O (10 mL). The sample was neutralizedwith solid Na₂CO₃ and the aqueous layer extracted with CH₂Cl₂ (3×10 mL).The combined organic extracts were dried (MgSO₄), evaporated to give thetitle compound as a yellow oil (5 mg, 10% yield). ¹H NMR (300 MHz,CDCl₃) δ 7.92 (d, 2H, J=8.3), 7.91 (s, 1H), 7.44 (d, 2H, J=8.3),7.45-7.43 (m, 1H), 7.33-7.32 (m, 1H), 6.63 (s, 1H), 4.63-4.56 (m, 4H),3.68 (t, 2H, J=6.0), 3.07 (s, 3H), 2.61 (s, 3H), 2.05 (t, 2H, J=6.0).Mass spectrum (API-TIS) m/z 491 (M+1).

Example 411-(3-((1E)-3-(Nitrooxy)prop-1-enyl)-1-cyclohexylpyrazol-5-yl)-4-(methylsulfonyl)benzene

The title compound was prepared as a white foam from the product ofExample 31c (33 mg, 0.09 mmol) in CHCl₃ (0.3 mL), fuming HNO₃ (19 μL, 29mg, 0.46 mmol) and Ac₂O (69 μL, 74.9 mg, 0.73 mmol) following theprocedure for the preparation of Example 1h. ¹H NMR (300 MHz, CDCl₃) δ8.06 (d, J=8.3 Hz, 2H), 7.57 (d, J=6.7 Hz, 2H), 6.84 (d, J=16.0 Hz, 1H),6.44 (s, 1H), 6.20-6.30 (m, 1H), 5.07 (d, J=6.8 Hz, 2H), 3.89-4.10 (m,1H), 3.14 (s, 3H), 1.92-2.10 (m, 2H), 1.78-1.92 (m, 4H), 1.57-1.75 (m,2H), 1.15-1.35 (m, 2H). Mass spectrum (API-TIS) m/z 406 (MH⁺).

Example 424-(5-(4-(Methylsulfonyl)phenyl)-3-(4-(nitrooxy)butanoyl)pyrazolyl)benzenecarbonitrile 42a. Methyl1-(4-cyanophenyl)-5-(4-methylthiophenyl)pyrazole-3-carboxylate

The title compound was prepared from the product of Example 1d (5 g, 20mmol) and 4-cyanophenylhydrazine hydrochloride (4.4 g, 26 mmol) inacetic acid (120 mL) following the procedure for the preparation ofExample 1e. Purification gave a yellow solid (5.3 g, 76% yield). Mp177-179° C. ¹H NMR (300 MHz, CDCl₃) δ 7.66 (d, J=8.7 Hz, 2H), 7.48 (d,J=8.7 Hz, 2H), 7.21 (d, J=8.5 Hz, 2H), 7.11 (d, J=8.5 Hz, 2H), 7.03 (s,1H), 3.98 (s, 3H), 2.50 (s, 3H); Mass spectrum (API-TIS) m/z 350 (MH⁺);Anal. calcd for C₁₉H₁₅N₃O₂S: C, 65.31; H, 4.33; N, 12.03. Found: C,65.37; H, 4.12; N, 12.01.

42b.1-(4-Cyanophenyl)-5-(4-methylthiophenyl)-pyrazol-3-yl)carboxamido-N-methoxy-N-methyl

The title compound was prepared from the product of Example 42a (1.77 g,5.05 mmol), trimethylaluminum (5.05 mL of 2M solution in hexane, 0.73 g,10.1 mmol) and dimethylhydroxylamine hydrochloride (0.99 g, 10.1 mmol)following the procedure for the preparation of Example 3c. Purificationgave a white solid (1.8 g, 94% yield). Mp 146-147° C. ¹H NMR (300 MHz,CDCl₃) δ 7.66 (d, J=8.2 Hz, 2H), 7.49 (d, J=8.3 Hz, 2H), 7.23 (d, J=8.2Hz, 2H), 7.15 (d, J=8.2 Hz, 2H), 6.98 (s, 1H), 3.85 (s, 3H), 3.49 (br s,3H), 2.51 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 147.1, 143.7, 143.0, 140.8,133.1, 129.2, 126.2, 125.6, 125.4, 118.1, 111.5, 111.2, 61.8, 34.0,15.2; Mass spectrum (API-TIS) m/z 379 (MH⁺). Anal. calcd forC₂₀H₁₈N₄O₂S.¼ mol H₂O: C, 62.72; H, 4.87; N, 14.63. Found: C, 62.70; H,4.82; N, 14.57.

42c.4-(5-(4-Methylthiophenyl)-3-(4-(1,1,2,2-tetramethyl-1-silapropoxy)butanoyl)pyrazolyl)benzenecarbonitrile

The title compound was prepared from the product of Example 42b (1.56 g,4.12 mmol), the Grignard reagent (35 mL) (prepared from3-bromo-1-(1,1,2,2-tetramethyl-1-silapropoxy)propane (25 g, 98.8 mmol)and magnesium turnings (4.98 g, 0.21 mol) in THF (180 mL) following theprocedure for the preparation of Example 3d. Purification gave a whitesolid (1.5 g, 73% yield). Mp 91-93° C. ¹H NMR (300 MHz, CDCl₃) δ 7.67(d, J=8.6 Hz, 2H), 7.48 (d, J=8.5 Hz, 2H), 7.21 (d, J=8.4 Hz, 2H), 7.11(d, J=8.3 Hz, 2H), 6.98 (s, 1H), 3.72 (t, J=6.3 Hz, 2H), 3.15 (t, J=7.3Hz, 2H), 2.50 (s, 3H), 1.99 (p, J=7.0 Hz, 2H), 0.88 (s, 9H), 0.05 (s,6H); ¹³C NMR (75 MHz, CDCl₃) δ 196.3, 152.4, 144.8, 143.1, 141.0, 133.2,129.2, 126.2, 125.5, 125.5, 118.1, 111.7, 108.8, 62.6, 35.4, 27.4, 26.1,18.4, 15.2, −5.2; Mass spectrum (API-TIS) m/z 492 (MH⁺). Anal. calcd.for C₂₇H₃₃N₃O₂SSi: C, 65.95; H, 6.76; N, 8.55. Found: C, 65.89; H, 6.69;N, 8.44.

42d.4-(3-(4-Hydroxybutanoyl)-5-(4-(methylsulfonyl)phenyl)pyrazolyl)benzenecarbonitrile

The title compound was prepared from the product of Example 42c (1.5 g,3.06 mmol) in MeOH (54 mL) and OXONE® (5.6 g, 9.17 mmol) in water (18mL) following the procedure for the preparation of Example 12d.Purification gave a white solid (0.64 g, 52% yield). Mp 169-171° C. ¹HNMR (300 MHz, CDCl₃) δ 7.97 (dd, J=1.9 and 6.7 Hz, 2H), 7.72 (dd, J=2.0and 10.8 Hz, 2H), 7.40-7.50 (m, 4H), 7.12 (s, 1H), 3.76 (q, J=6.0 Hz,2H), 3.24 (t, J=7.0 Hz, 2H), 3.10 (s, 3H), 2.06 (p, J=6.3 Hz, 2H), 1.79(t, J=3.2 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 196.2, 152.5, 143.3, 142.4,141.5, 134.5, 133.6, 129.7, 128.3, 125.7, 117.7, 112.7, 110.1, 62.4,44.5, 35.7, 27.1; Mass spectrum (API-TIS) m/z 410 (MH⁺), 392 (M-OH).Anal. calcd. for C₂₁H₁₉N₃O₄S: C, 61.60; H, 4.68; N, 10.26. Found: C,61.34; H, 4.50; N, 10.18.

42e.4-(5-(4-(Methylsulfonyl)phenyl)-3-(4-(nitrooxy)butanoyl)pyrazolyl)benzenecarbonitrile

The title compound was prepared from the product of Example 42d (0.4 g,0.98 mmol) in CHCl₃ (3.2 mL), fuming HNO₃ (0.21 mL, 0.31 g, 4.89 mmol)and Ac₂O (0.74 mL, 0.80 g, 7.8 mmol) following the procedure for thepreparation of Example 1h. Purification gave a white solid (0.32 g, 72%yield). Mp 148-149° C. ¹H NMR (300 MHz, CDCl₃) δ 7.96 (d, J=8.3 Hz, 2H),7.72 (dd, J=1.8 and 8.5 Hz, 2H), 7.40-7.50 (m, 4H), 7.12 (s, 1H), 4.59(t, J=6.3 Hz, 2H), 3.25 (t, J=7.1 Hz, 2H), 3.10 (s, 3H), 2.22 (p, J=6.9Hz, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 194.2, 152.2, 143.4, 142.3, 141.5,134.4, 133.6, 129.7, 128.3, 125.7, 117.7, 112.8, 110.0, 72.5, 44.5,34.7, 21.3; Mass spectrum (API-TIS) m/z 455 (MH⁺), 472 (MNH₄ ⁺). Anal.cacld. for C₂₁H₁₈N₄O₆S.0.1 mol EtOAc: C, 55.48; H, 4.09; N, 12.09.Found: C, 55.36; H, 4.02; N, 11.78.

Example 434-(1-Cyclohexyl-3-(4-(nitrooxy)butanoyl)pyrazol-5-yl)benzenesulfonamide43a.(1-Cyclohexyl-5-(4-(methylthiophenyl)pyrazol-3-yl)-N-methoxy-N-methylcarboxamide

The title compound was prepared from Example 4a (7 g, 21.2 mmol),trimethylaluminum (21.1 mL of 2M solution in hexane, 3.05 g, 42.4 mmol)and dimethylhydroxylamine hydrochloride (4.13 g, 42.4 mmol) followingthe procedure for the preparation of Example 3c. Purification gave awhite solid (7.1 g, 93% yield). Mp 80-82° C. ¹H NMR (300 MHz, CDCl₃) δ7.34 (d, J=6.4 Hz, 2H), 7.27 (d, J=8.0 Hz, 2H), 6.71 (s, 1H), 4.05-4.20(m, 1H), 3.84 (s, 3H), 3.48 (s, 3H), 2.54 (s, 3H), 1.80-2.10 (m, 6H),1.56-1.70 (m, 1H), 1.17-1.32 (m, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 144.2,142.9, 139.9, 129.5, 126.9, 126.4, 108.6, 61.6, 58.4, 33.4, 25.6, 25.2,15.5; Mass spectrum (API-TIS) m/z 360 (MH⁺). Anal. calcd. forC₁₉H₂₅N₃O₂S: C, 63.48; H, 7.01; N, 11.69. Found: C, 63.72; H, 7.05; N,11.75.

43b.1-(1-Cyclohexyl-5-(4-methylthiophenyl)pyrazol-3-yl)-4-(1,1,2,2-tetramethyl-1-silapropoxy)butan-1-one

The title compound was prepared from the product of Example 43a (3.9 g,11.0 mmol) in THF (30 mL), the Grignard reagent prepared from3-bromo-1-(1,1,2,2-tetramethyl-1-silapropoxy)propane (25 g, 98.8 mmol)and magnesium turnings (5.0 g, 20.8 mol) in THF (180 mL) following theprocedure for preparation of Example 3d. Purification gave a colorlessoil (3.79 g, 48% yield). ¹H NMR (300 MHz, CDCl₃) δ 7.20-7.38 (m, 4H),6.71 (s, 1H), 4.02-4.20 (m, 1H), 3.72 (t, J=6.4 Hz, 2H), 3.10 (t, J=7.3Hz, 2H), 2.54 (s, 3H), 1.72-2.05 (m, 10H), 1.19-1.32 (m, 2H), 0.91 (s,9H), 0.06 (s, 6H); Mass spectrum (API-TIS) m/z 473 (MH⁺).

43c.1-(1-Cyclohexyl-5-(4-(methylsulfinyl)phenyl)pyrazol-3-yl)-4-(1,1,2,2-tetramethyl-1-silapropoxy)butan-1-one

The product of Example 43b (3.23 g, 6.84 mmol) was dissolved in CH₂Cl₂(48 mL) and MeOH (15 mL). Magnesium monoperoxyphathalate hexahydrate(MMPP) (1.83 g, 3.69 mmol) was added in five equal portions at 1 minuteintervals. The resulting heterogeneous solution was stirred at roomtemperature for 1 hour. Saturated NaHCO₃ was added. The organic layerwas separated, dried over Na₂SO₄ and the solvent was evaporated in vacuoto give the crude product. The crude product was chromatographed onsilica gel eluting with 10% MeOH/CH₂Cl₂ to give the title compound (1.5g, 45% yield) as an oil. ¹H NMR (300 MHz, CDCl₃) δ 7.77 (d, J=8.3 Hz,2H), 7.51 (d, J=8.3 Hz, 2H), 6.78 (s, 1H), 3.98-4.20 (m, 1H), 3.72 (t,J=6.4 Hz, 2H), 3.12 (t, J=7.3 Hz, 2H), 2.81 (s, 3H), 1.78-2.10 (m, 10H),1.14-1.33 (m, 2H), 0.90 (s, 9H), 0.06 (s, 6H); ¹³C NMR 6 (75 MHz, CDCl₃)196.6, 150.2, 146.7, 143.0, 133.3, 130.0, 124.3, 106.8, 62.7, 58.8,44.0, 35.3, 33.4, 27.6, 26.1, 25.6, 25.1, 18.4, −5.3; Mass spectrum(API-TIS) m/z 488 (MH⁺). Anal. calcd. for C₂₆H₃₉N₂O₃SSi: C, 64.03; H,8.06; N, 5.74. Found: C, 63.86; H, 8.05; N, 5.74.

43d.(4-(1-Cyclohexyl-3-(4-(1,1,2,2-tetramethyl-1-silapropoxy)butanoyl)pyrazol-5-yl)phenylthio)methylacetate

The product of Example 43c (1.5 g, 3.1 mmol) was dissolved in aceticanhydride (12 mL). Powdered sodium acetate (1.1 g, 13.4 mmol) was addedand the solution was refluxed for 8 hour. The solvent was evaporated invacuo. The residue was taken up in EtOAc:CH₂Cl₂ (1:0.5), washed withsaturated NH₄Cl, brine and dried over Na₂SO₄. The solvent was removedunder vacuo to give the title compound (0.9 g, 56% yield) as oil. ¹H NMR(300 MHz, CDCl₃) δ 7.54 (d, J=8.3 Hz, 2H), 7.31 (d, J=8.3 Hz, 2H), 6.73(s, 1H), 5.49 (s, 2H), 4.00-4.18 (m, 1H), 3.73 (t, J=6.4 Hz, 2H), 3.11(t, J=7.3 Hz, 2H), 2.15 (s, 3H), 1.83-2.00 (m, 10H), 1.12-1.32 (m, 2H),0.91 (s, 9H), 0.06 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 196.8, 170.3,150.1, 143.5, 136.3, 129.8, 129.2, 106.5, 67.4, 62.8, 58.6, 35.3, 33.4,27.7, 26.1, 25.6, 25.2, 21.2, 18.4, −5.2; Mass spectrum (API-TIS) m/z531 (MH⁺). Anal. calcd. for C₂₈H₄₂N₂O₄SSi: C, 63.36; H, 7.98; N, 5.28.Found: C, 63.32; H, 7.81; N, 5.19.

43e.((4-(1-Cyclohexyl-3-(4-(1,1,2,2-tetramethyl-1-silapropoxy)butanoyl)pyrazol-5-yl)phenyl)sulfonyl)methyl acetate

The product of Example 43d (0.9 g, 1.7 mmol) and MMPP (0.92 g, 1.86mmol) were mixed in CH₂Cl₂ (16 mL) and MeOH (5 mL) and was stirred atroom temperature for 16 hours. The reaction mixture was neutralized withsaturated NaHCO₃ and the solvent was evaporated to half of its volume.The residue was extracted into CH₂Cl₂, washed with saturated NaHCO₃,water, dried over Na₂SO₄, filtered and evaporated to give the titlecompound (0.74 g, 78% yield) as an oil. ¹H NMR (300 MHz, CDCl₃) δ 8.05(d, J=8.3 Hz, 2H), 7.58 (d, J=8.3 Hz, 2H), 6.83 (s, 1H), 5.21 (s, 2H),3.98-4.12 (m, 1H), 3.73 (t, J=6.3 Hz, 2H), 3.12 (t, J=7.4 Hz, 2H), 2.13(s, 3H), 1.82-2.10 (m, 9H), 1.20-1.35 (m, 1H), 1.20-1.35 (m, 2H), 0.89(s, 9H), 0.06 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 196.4, 168.3, 150.4,142.2, 137.3, 136.7, 130.0, 129.6, 107.3, 62.7, 59.1, 35.3, 34.8, 33.4,31.7, 27.6, 26.1, 25.5, 25.1, 22.8, 20.4, 18.4, 14.2, −5.1; Massspectrum (API-TIS) m/z 563 (MH⁺). Anal. calcd. for C₂₈H₄₂N₂O₆SSi: C,59.76; H, 7.52; N, 4.98. Found: C, 59.67; H, 7.37; N, 4.94.

43f.4-(1-Cyclohexyl-3-(4-(1,1,2,2-tetramethyl-1-silapropoxy)butanoyl)pyrazol-5-yl)benzenesulfonamide

Sodium acetate (0.77 g, 9.4 mmol) was added to a solution of the productof Example 43e (0.66 g, 1.17 mmol) in methanol (14 mL). The resultantmixture was stirred at room temperature for 15 minutes K₂CO₃ (0.46 g,3.3 mmol) was added and the stirring was continued for 1.5 hours. Tothis solution, hydroxyaminosulfonic acid (0.53 g, 4.69 mmol) was added.The mixture was stirred at room temperature for 2 hours, diluted withEtOAc and saturated NaHCO₃ was added. The solvent was evaporated to asmall volume, more EtOAc was added. The organic layer was washed withsaturated NaHCO₃, brine, dried over Na₂SO₄ and filtered. The residueafter evaporation of the solvent was chromatographed on silica geleluting with 1:2 to 1:1 EtOAc:Hexane to give the title compound (0.38 g,64% yield) as a white solid. Mp 151-153° C. ¹H NMR (300 MHz, CDCl₃) δ8.04 (d, J=8.4 Hz, 2H), 7.50 (d, J=8.4 Hz, 2H), 6.78 (s, 1H), 4.96 (s,2H), 3.92-4.10 (m, 1H), 3.72 (t, J=6.3 Hz, 2H), 3.12 (t, J=7.3 Hz, 2H),1.75-2.10 (m, 8H), 1.48-1.60 (m, 2H), 1.20-1.38 (m, 2H), 0.90 (s, 9H),0.06 (s, 6H); Mass spectrum (API-TIS) m/z 506 (MH⁺).

43g.4-(1-Cyclohexyl-3-(4-hydroxybutanoyl)pyrazol-5-yl)benzenesulfonamide

Tetrabutylammonium fluoride (0.75 mL of 1M solution in THF, 0.20 g, 0.75mmol) was added dropwise to a solution of the product of Example 43f(0.38 g, 0.75 mmol) in THF (9 mL). The reaction mixture was stirred atroom temperature for 16 hours. The residue after evaporation of thesolvent was chromatographed on silica gel eluting with 1:1 EtOAc:CH₂Cl₂to give the title compound (0.23 g, 78% yield) as a white solid. Mp152-154° C. ¹H NMR (300 MHz, d₆-DMSO) δ 7.95 (d, J=8.4 Hz, 2H), 7.68 (d,J=8.4 Hz, 2H), 6.84 (s, 1H), 4.48 (t, J=5.2 Hz, 2H), 4.08-4.22 (m, 1H),3.42-3.49 (m, 2H), 3.02 (t, J=7.4 Hz, 2H), 1.82-2.00 (m, 4H), 1.70-1.82(m, 4H), 1.19-1.38 (m, 2H); ¹³C NMR (75 MHz, d₆-DMSO) δ 195.2, 149.5,144.4, 143.0, 132.6, 129.6, 126.3, 106.6, 60.2, 58.1, 34.9, 32.9, 27.0,24.8, 24.7; Mass spectrum (API-TIS) m/z 374 (M-OH), 392 (MH⁺). LCMS(94.3%).

43h.4-(1-Cyclohexyl-3-(4-(nitrooxy)butanoyl)pyrazol-5-yl)benzenesulfonamide

The title compound was prepared from the product of Example 43g (0.15 g,0.38 mmol), fuming nitric acid (80 μL, 0.12 g, 1.92 mmol) and aceticanhydride (0.28 mL, 0.31 g, 3.1 mmol) following the procedure for thepreparation of Example 1h. Purification gave a white solid (0.12 g, 74%yield). Mp 45-47° C. ¹H NMR (300 MHz, d₆-DMSO) δ 8.05 (d, J=8.3 Hz, 2H),7.51 (d, J=8.2 Hz, 2H), 6.80 (s, 1H), 4.75-4.90 (m, 2H), 4.59 (t, J=6.3Hz, 2H), 3.90-4.20 (m, 1H), 3.21 (t, J=7.1 Hz, 2H), 2.15-2.24 (m, 2H),1.75-1.92 (m, 4H), 1.92-2.15 (m, 2H), 1.40-1.60 (m, 2H), 1.18-1.32 (m,2H); ¹³C NMR (75 MHz, d₆-DMSO) δ 194.9, 149.9, 142.8, 142.6, 134.7,129.8, 127.2, 107.1, 72.8, 59.1, 34.6, 33.4, 25.5, 25.1, 21.5; Massspectrum (API-TIS) m/z 437 (MH⁺). LCMS (94.6%).

Example 441-(1-(4-Chlorophenyl)-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-4-(nitrooxy)butan-1-one44a. Methyl1-(4-chlorophenyl)-5-(4-methylthiophenyl)pyrazol-3-carboxylate

The title compound was prepared from the product of Example 1d (5 g, 20mmol) and 4-chlorophenylhydrazine hydrochloride (4.7 g, 26 mmol) in MeOH(120 mL) following the procedure for the preparation of Example 1e.Purification gave a white solid (5.7 g, 79% yield). Mp 140-143° C. ¹HNMR (300 MHz, CDCl₃) δ 7.34 (d, J=8.8 Hz, 2H), 7.28 (d, J=8.8 Hz, 2H),7.19 (d, J=8.4 Hz, 2H), 7.11 (d, J=8.4 Hz, 2H), 7.01 (s, 1H), 3.97 (s,3H), 2.49 (s, 3H); Mass spectrum (API-TIS) m/z 359 (MH⁺). Anal. calcd.for C₁₈H₁₅ClN₂O₂S: C, 60.25; H, 4.21; N, 7.81. Found: C, 60.47; H, 4.10;N, 7.80.

44b.(1-(4-Chlorophenyl)-5-(4-methylthiophenyl)pyrazol-3-yl)-N-methoxy-N-methylcarboxamide

The title compound was prepared from the product of Example 44a (2.5 g,7.0 mmol), trimethylaluminum (7.0 mL of 2M solution in hexane, 1.00 g,13.9 mmol) and dimethylhydroxylamine hydrochloride (1.36 g, 13.9 mmol)following the procedure for the preparation of Example 3c. Purificationgave a white solid (2.3 g, 85% yield). Mp 128-129° C. ¹H NMR (300 MHz,CDCl₃) δ 7.08-7.35 (m, 8H), 6.96 (s, 1H), 3.85 (s, 3H), 3.50 (br s, 3H),2.49 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 162.6, 146.1, 143.3, 140.1,138.1, 133.7, 129.1, 129.0, 126.4, 125.9, 110.2, 61.6, 15.1; Massspectrum (API-TIS) m/z 388 (MH⁺). Anal. calcd. for C₁₉H₁₈ClN₃O₂S: C,58.83; H, 4.68; N, 10.83. Found: C, 58.58; H, 4.64; N, 10.66.

44c.1-(1-(4-Chlorophenyl)-5-(4-methylthiophenyl)pyrazol-3-yl)-4-(1,1,2,2-tetramethyl-1-silapropoxy)butan-1-one

The title compound was prepared from the product of Example 44b (2.3 g,5.9 mmol), the Grignard reagent (81 mL) (prepared from3-bromo-1-(1,1,2,2-tetramethyl-1-silapropoxy)propane (68 g, 0.27 mol)and magnesium turnings (13.5 g, 0.56 mol) in THF (500 mL) following theprocedure for the preparation of Example 3d. Purification gave a whitesolid (1.9 g, 65% yield). Mp 64-65° C. ¹H NMR (300 MHz, CDCl₃) δ7.02-7.42 (m, 8H), 6.96 (s, 1H), 3.72 (t, J=6.3 Hz, 2H), 3.15 (t, J=7.3Hz, 2H), 2.49 (s, 3H), 1.99 (p, J=6.8 Hz, 2H), 0.89 (s, 9H), 0.05 (s,6H); ¹³C NMR (75 MHz, CDCl₃) δ 196.5, 151.8, 144.5, 140.4, 138.3, 134.2,129.4, 129.1, 126.6, 126.2, 125.9, 108.0, 62.6, 35.3, 27.5, 26.1, 18.5,15.3, −5.2; Mass spectrum (API-TIS) m/z 502 (MH⁺). Anal. calcd. forC₂₆H₃₃ClN₂O₂SSi.¼ mol CHCl₃: C, 59.38; H, 6.31; N, 5.28. Found: C,59.00; H, 6.25; N, 5.04.

44d.1-(1-(4-Chlorophenyl)-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-4-hydroxybutan-1-one

The title compound was prepared from the product of Example 44c (1.9 g,3.8 mmol) in MeOH (57 mL) and OXONE® (7.0 g, 11.4 mmol) in water (19 mL)following the procedure for the preparation of Example 12d. Purificationgave a white solid (0.47 g, 29% yield). Mp 147-148° C. ¹H NMR (300 MHz,CDCl₃) δ 7.92 (d, J=8.3 Hz, 2H), 7.35-7.46 (m, 4H), 7.20-7.29 (m, 2H),7.10 (s, 1H), 3.74 (q, J=6.0 Hz, 2H), 3.23 (t, J=7.0 Hz, 2H), 3.08 (s,3H), 2.00-2.11 (m, 2H), 1.96 (t, J=5.6 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃)δ 196.4, 151.9, 143.1, 141.0, 135.0, 134.8, 129.9, 129.6, 128.1, 126.7,109.2, 62.4, 44.5, 35.6, 27.3; Mass spectrum (API-TIS) m/z 419 (MH⁺),401 (M-OH). Anal. calcld. for C₂₀H₁₉ClN₂O₄S: C, 57.35; H, 4.57; N, 6.69.Found: C, 56.97; H, 4.49; N, 6.36.

44e.1-(1-(4-Chlorophenyl)-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-4-(nitrooxy)butan-1-one

The title compound was prepared from the product of Example 44d (0.19 g,0.45 mmol) in CHCl₃ (2 mL), fuming HNO₃ (95.4 μL, 0.14 g, 2.27 mmol) andAc₂O (0.34 mL, 0.37 g, 3.6 mmol) following the procedure for thepreparation of Example 1h. Purification gave a white solid. Mp 131-132°C. ¹H NMR (300 MHz, CDCl₃) δ 7.92 (d, J=8.1 Hz, 2H), 7.30-7.48 (m, 4H),7.15-7.30 (m, 2H), 7.10 (s, 1H), 4.58 (t, J=6.3 Hz, 2H), 3.25 (t, J=7.0Hz, 2H), 3.08 (s, 3H), 2.22 (p, J=6.6 Hz, 2H); ¹³C NMR (75 MHz, CDCl₃) δ194.3, 151.5, 143.1, 141.0, 137.6, 135.1, 134.7, 129.8, 129.6, 128.0,126.7, 109.1, 72.6, 44.5, 34.6, 21.2; Mass spectrum (API-TIS) m/z 464(MH⁺). Anal. calcd. for C₂₀H₁₈ClN₃O₆S: C, 51.78; H, 3.91; N, 9.06.Found: C, 51.54; H, 3.86; N, 8.87.

Example 45(1-Cyclohexyl-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-N-(2-(nitrooxy)ethyl)carboxamide(NMI-1693) 45a.(1-Cyclohexyl-5-(4-methylthiophenyl)pyrazol-3-yl)-N-(2-hydroxyethyl)carboxamide

The product of Example 4b (1.8 g, 5.45 mmol) and ethanolamine (12 ml,198.82 mmol) were heated at 60° C. for 2 hours. The mixture was allowedto warm to room temperature and acidified with 1N HCl. The reactionmixture was extracted with ether (3×10 mL) and the organics separated,dried over MgSO₄ and the solvent removed under reduced pressure to givea yellow oil. The sample was triturated in Et₂O to give the titlecompound as a pale yellow solid (998 mg, 50% yield). Mp 149-151 0° C. ¹HNMR (300 MHz, CDCl₃); δ 7.33 (d, J=8.3, 2H), 7.25 (d, J=8.3, 2H), 6.73(s, 1H), 4.07-4.06 (m, 1H) 3.84 (t, J=4.9, 2H), 3.64-3.59 (m, 2H), 2.53(s, 3H), 1.95-1.90 (m, 3H), 1.86-1.85 (m, 3H), 1.28-1.25 (m, 3H). Massspectrum (API-TIS) m/z 360 (M+1).

45b.(1-Cyclohexyl-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-N-(2-hydroxyethyl)carboxamide

The product of Example 45a (540 mg, 1.50 mmol) was cooled to 0° C. anddissolved in MeOH/H₂O (20 mL/10 mL). OXONE® was added (1.20 g, 1.95mmol) and the mixture stirred at 0° C. for 1 hour. The mixture wasallowed to warm to room temperature and stirred for an additional hour.The resulting solid was removed by filtration and the filtrate madebasic with saturated Na₂CO₃ solution. Additional H₂O (10 mL) was addedand the sample extracted with EtOAc (3×30 mL). The combined organicextracts were dried over MgSO₄ and the solvent removed under reducedpressure to give the title compound as a solid (94.5 mg, 15% yield). Mp199-201° C. ¹H NMR (300 MHz, CDCl₃); δ 8.06 (d, J=8.1, 2H), 7.56 (d,J=8.1, 2H), 7.56-7.32 (m, 1H), 6.84 (s, 1H), 4.06-4.02 (m, 1H) 3.85-3.83(m, 2H), 3.65-3.60 (m, 2H), 3.12 (s, 3H), 2.03-2.02 (m, 2H), 1.98-1.87(m, 2H), 1.70 (br s, 1H), 1.61 (br s, 1H), 1.27-1.25 (m, 3H). Massspectrum (API-TIS) m/z 392 (M+1).

45c.(1-Cyclohexyl-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-N-(2-(nitrooxy)ethyl)carboxamide

Fuming nitric acid (700 μL, 17.55 mmol) was added to acetic anhydride(756.6 μL, 8.01 mmol) at 0° C. and the mixture stirred for 10 minutes.The mixture was then added to a solution of the product of Example 45b(85.9 mg, 0.22 mmol) in EtOAc (15 mL) at 0° C. and the mixture stirredfor 2 hours. Saturated NaHCO₃ was added to basify the mixture and theorganic layer was separated. The aqueous layer was washed withadditional EtOAc (2×10 mL) and the combined organic layers were driedover MgSO₄ and the solvent removed under reduced pressure to give thetitle compound (69.7 mg, 73% yield) as a solid. Mp 168-170° C. ¹H NMR(300 MHz, CDCl₃); δ 8.06 (d, J=8.2, 2H), 7.56 (d, J=8.2, 2H), 7.20-7.16(m, 1H), 6.83 (s, 1H), 4.67 (t, J=5.3, 2H), 4.08-4.00 (m, 1H) 3.81 (q,J=5.3, 2H), 3.11 (s, 3H), 2.10-1.89 (m, 5H), 2.10 (br s, 1H), 1.17 (brs, 1H), 1.28-1.25 (m, 3H). Mass spectrum (API-TIS) m/z 437 (M+1).

Example 46(1-Cyclohexyl-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-N-(3-(nitrooxy)propyl)carboxamide 46a.(1-Cyclohexyl-5-(4-methylthiophenyl)pyrazol-3-yl)-N-(3-hydroxypropyl)carboxamide

The product of Example 4b (540.0 mg, 1.64 mmol) and propanolamine (7 ml,91.5 mmol) were heated at 60° C. overnight. The sample was allowed tocool to room temperature and diluted with EtOAc (30 mL). The solutionwas pulled through a silica gel plug to remove any excess propanolamine.The filtrate was collected and the solvent removed under reducedpressure to give an oil, which upon standing at room temperature yieldedan oil/crystal mixture. Et₂O was added and the crystals collected viafiltration. The sample was purified via recrystallization fromhexanes/CH₂Cl₂ to give the title compound (329.8 mg, 54% yield) as whitecrystals. ¹H NMR (300 MHz, CDCl₃); δ 7.33 (d, J=8.4, 2H), 7.24 (d,J=8.4, 2H), 7.17 (m, 1H), 6.73 (s, 1H), 4.06-4.04 (m, 1H) 3.68 (t,J=5.7, 2H), 3.61 (q, J=5.7, 2H), 2.53 (s, 3H), 1.99-1.95 (m, 2H),1.91-1.82 (m, 3H), 1.78 (t, J=5.7, 2H), 1.68 (m, 1H), 1.26 (m, 3H). Massspectrum (API-TIS) m/z 374 (M+1).

46b.(1-Cyclohexyl-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-N-(3-hydroxypropyl)carboxamide

The product of Example 46a (392.8 mg, 0.88 mmol) was dissolved inMeOH/H₂O (10 mL/5 mL) and OXONE® was added (3.7 mg, 6.02 mmol). Themixture was stirred at room temperature for 4 hours. The resultingprecipitate was removed via filtration and the solid washed with MeOH (2mL). The filtrate was collected and diluted with additional CH₂Cl₂ (10mL). The organic layer was separated and the aqueous portion extractedwith additional CH₂Cl₂ (2×10 mL). The combined organic extracts werecollected, dried over MgSO₄ and the solvent removed under reducedpressure to give the title compound (196.2 mg, 55% yield) as a whitesolid. Mp 166-168° C. ¹H NMR (300 MHz, CDCl₃); δ 8.04 (d, J=8.0, 2H),7.54 (d, J=8.0, 2H), 7.24-7.21 (m, 1H), 6.81 (s, 1H), 4.06-3.99 (m, 1H)3.66-3.49 (m, 4H), 3.11 (s, 3H), 2.00-1.68 (m, 8H), 1.26-1.24 (m, 3H).Mass spectrum (API-TIS) m/z 406 (M+1).

46c. (1-Cyclohexyl-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl)-N-(3(nitrooxy) propyl)carboxamide

Fuming nitric acid (10 mL, 250.7 mmol) was cooled to −10° C. and theproduct of Example 46b (80.3 mg, 0.19 mmol) was added as a solid. Themixture was stirred at −10° C. for 1.5 hours and diluted with ice water.The mixture was neutralized with a saturated solution of Na₂CO₃ andextracted with EtOAc (3×15 mL). The combined organic extracts werewashed with brine, and dried over MgSO₄. The solvent was removed underreduced pressure to give the title compound (60.8 mg, 68% yield) a paleyellow solid. Mp 168-170° C. ¹H NMR (300 MHz, CDCl₃); δ 8.06 (d, J=8.2,2H), 7.56 (d, J=8.2, 2H), 7.10-7.08 (m, 1H), 6.82 (s, 1H), 4.59 (t,J=6.5, 2H), 4.07-4.02 (m, 1H) 3.57 (q, J=6.5, 2H), 3.12 (s, 3H),2.14-1.99 (m, 4H), 2.10 (t, J=6.5, 2H), 1.70 (br s, 1H), 1.63 (br s,1H), 1.27-1.25 (m, 3H). Mass spectrum (API-TIS) m/z 437 (M+1).

Example 47 3-(Nitrooxy)propyl4-(5-(4-(methylsulfonyl)phenyl)-1-(4-(trifluoromethyl)phenyl)pyrazol-3-yl)butanoate47a. Methyl (6Z)-7-hydroxy-7-(4-methylthiophenyl)-5-oxohept-6-enoate

Lithium diisopropylamide mono(tetrahydrofuran) in cyclohexane (1.5 M; 28mL, 42 mmol) was added to a solution of1-(4-methylthiophenyl)ethan-1-one (5.16 g, 31 mmol) in THF (120 mL) andstirred for 30 minutes at −72° C. A solution of methyl4-(chloroformyl)butyrate (1.78 g, 10.8 mmol) was added to the abovesolution and stirred for 30 minutes and then warmed slowly from the −72°C. to −45° C. To the reaction mixture was added 3N HCl (50 mL) andextracted with ethyl acetate (100 mL×3). The combined organic layerswere washed with water, brine, dried over Na₂SO₄, filtered andevaporated. Trituration of the residue with diethyl ether/hexane gave amixture of the title compound and starting material (˜30% yield) as asolid (2.42 g). The crude material was used in the next step withoutpurification. A small quantity of pure sample was obtained at thebeginning of the trituation. Mp. 92-93° C. ¹H NMR (CDCl₃) δ 15.1 (br,1H), 7.79 (d, J=8.6 Hz, 2H), 7.27 (d, J=8.6 Hz, 2H), 6.13 (s, 1H), 3.69(s, 3H), 2.52 (s, 3H), 2.48 (t, J=7.4 Hz, 2H), 2.42 (t, J=7.4 Hz, 2H),2.02 (m, 2H). ¹³C NMR (CDCl₃) δ 194.8, 183.0, 173.4, 144.9, 131.0,127.3, 125.2, 95.6, 51.5, 37.9, 33.1, 20.8, 14.8.

47b. Methyl4-(5-(4-methylthiophenyl)-1-(4-(trifluoromethyl)phenyl)pyrazol-3-yl)butanoate

A solution of the product of Example 47a (1.61 g) and4-(trifluoromethyl) phenylhydrazine hydrochloride (1.28 g, 7.3 mmol) inmethanol (50 mL) was heated at reflux for 4 hours. The reaction wasconcentrated and the residue was separated by silica gel columnchromatography eluting with ethyl acetate/hexane (1:4, Rf=0.2) to give amixture of the title compound with some unknown impurities (˜5% yield)as an oil (1.80 g). The crude material was used in the next step withoutpurification. ¹H NMR (CDCl₃) δ 7.57 (d, J=8.4 Hz, 2H), 7.41 (d, J=8.4Hz, 2H), 7.18 (d, J=8.4 Hz, 2H), 7.13 (d, J=8.4 Hz, 2H), 6.33 (s, 1H),3.68 (s, 3H), 2.76 (t, J=7.6 Hz, 2H), 2.48 (s, 3H), 2.46 (t, J=7.4 Hz,2H), 2.09 (m, 2H). ¹³C NMR (CDCl₃) δ 173.7, 153.8, 143.4, 142.4, 139.6,128.9, 128.7 (J_(CF)=33 Hz), 126.6, 126.0, 125.9, 124.6, 123.8(J_(CF)=270 Hz), 51.4, 33.5, 27.5, 24.5, 15.1. MS (API) m/z 435 (M+H)⁺.

47c.4-(5-(4-Methylthiophenyl)-1-(4-(trifluoromethyl)phenyl)pyrazol-3-yl)butanoicacid

A solution of the product of Example 47b (1.80 g) and LiOH (0.11 g, 4.47mmol) in a mixture of water (10 mL), methanol (40 mL) and THF (30 mL)was stirred at room temperature overnight. The reaction mixture wasacidified with 3N HCl and then evaporated. The aqueous residue wasextracted with CH₂Cl₂ (30 mL×2). The combined organic extracts werewashed with water, brine, dried over Na₂SO₄, filtered and evaporated.The residue was separated by silica gel column chromatography elutingwith ethyl acetate/hexane (gradient from 1:2 to 3:2, Rf=0.3 in 3:2) togive the title compound as a white solid (0.82 g). Mp 92-93° C. ¹H NMR(CDCl₃) δ 7.58 (d, J=8.4 Hz, 2H), 7.41 (d, J=8.4 Hz, 2H), 7.19 (d, J=8.4Hz, 2H), 7.12 (d, J=8.4 Hz, 2H), 6.33 (s, 1H), 2.80 (t, J=7.4 Hz, 2H),2.50 (t, J=7.4 Hz, 2H), 2.49 (s, 3H), 2.09 (m, 2H). ¹³C NMR (CDCl₃) δ179.0, 153.7, 143.6, 142.6, 139.7, 129.1, 128.8 (J_(CF)=32 Hz), 126.5,126.1, 126.0, 124.8, 123.8 (J_(CF)=270 Hz), 33.5, 27.3, 24.3, 15.2. MS(API) m/e 419 (M−H)⁻. Analysis for C₂₁H₁₉F₃N₂O₂S Calcd. C, 59.99; H,4.55; N, 6.66. Found C, 59.72; H, 4.34; N, 6.60.

47d.4-(5-(4-(Methylsulfonyl)phenyl)-1-(4-(trifluoromethyl)phenyl)pyrazol-3-yl)butanoicacid

A solution of OXONE® (1.3 g, 2.11 mmol) in water (15 mL) was added to asolution of the product of Example 47c (0.82 g, 1.95 mmol) in methanol(50 mL) and stirred at room temperature for 1.5 hours. The reactionmixture was filtered though Celite and then evaporated. The residue waspartitioned between ethyl acetate and water. The organic layer was driedover Na₂SO₄, filtered and evaporated. The residue was separated bysilica gel column chromatography eluting with ethyl acetate/hexane(gradient from 1:2 to 2:3, Rf=0.1 in 1:2) to give the title compound asan oil. Trituration of the product with ether/hexane gave the titlecompound as a white solid (0.49 g, 55% yield). Mp 155-156° C. ¹H NMR(CDCl₃) δ 7.91 (d, J=8.4 Hz, 2H), 7.63 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.4Hz, 2H), 7.41 (d, J=8.4 Hz, 2H), 6.48 (s, 1H), 3.10 (s, 3H), 2.82 (t,J=7.4 Hz, 2H), 2.50 (t, J=7.4 Hz, 2H), 2.10 (m, 2H). ¹³C NMR (CDCl₃) δ178.9, 154.0, 142.1, 141.8, 140.2, 135.4, 129.4 (J_(CF)=32 Hz), 129.3,127.8, 126.3, 124.9, 123.8 (J_(CF)=270 Hz), 44.3, 33.3, 27.2, 24.1. MS(API) m/e 451 (M−H)⁻.

47e. 3-(Nitrooxy)propylamine nitric acid salt

A solution of 3-amino-1-propanol (6.17 g, 82.2 mmol) was added,dropwise, to an ice-cooled solution of fuming nitric acid (12 mL) inacetic anhydride (50 mL). The reaction was stirred in an ice-bath for 10minutes and then at room temperature for 10 minutes. The solvent wasevaporated under vacuum at 40° C. The residue was stirred in diethylether (200 mL) until the product precipitated. The mixture was filteredand the white crystalline solid was dried in vacuo to give the titlecompound (12.1 g, 80% yield). ¹H NMR (DMSO-d₆) δ 4.57 (br. t, 2H),2.8-3.0 (m, 2H), 1.96 (m, 2H). ¹³C NMR (DMSO-d₆) δ 70.9, 36.1, 24.5. MS(API) m/z 121 (M-NO₃)⁺.

47f. 3-(Nitrooxy)propyl4-(5-(4-(methylsulfonyl)phenyl)-1-(4-(trifluoromethyl)-phenyl)pyrazol-3-yl)butanoate

A solution of the product of Example 47d (0.35 g, 0.78 mmol), Example47e (0.18 g, 0.98 mmol), 4-dimethylaminopyridine (0.20 g, 0.16 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.21 g,1.11 mmol) and NEt₃ (0.4 mL, 2.87 mmol) in CH₂Cl₂ (30 mL) was stirred atroom temperature overnight. The reaction mixture was partitioned between3N HCl (50 mL) and CH₂Cl₂ (50 mL). The organic layer was washed withwater and brine, dried over Na₂SO₄, filtered and evaporated. The productwas separated by silica gel column chromatography eluting with ethylacetate (Rf=0.25) to give the title compound as a yellowish foam (0.257g, 59% yield). ¹H NMR (CDCl₃) δ 7.91 (d, J=8.4 Hz, 2H), 7.63 (d, J=8.4Hz, 2H), 7.44 (d, J=8.4 Hz, 2H), 7.38 (d, J=8.4 Hz, 2H), 6.49 (s, 1H),6.39 (br. t, 1H), 4.51 (t, J=6.3 Hz, 2H), 3.37 (q, J=6.3 Hz, 2H), 3.10(s, 3H), 2.77 (t, J=7.4 Hz, 2H), 2.33 (t, J=7.4 Hz, 2H), 2.05 (m, 2H),1.94 (m, 2H). ¹³C NMR (CDCl₃) δ 173.0, 154.1, 142.1, 141.7, 140.1,135.4, 129.3 (J_(CF)=32 Hz), 129.2, 127.6, 126.3, 124.7, 123.5(J_(CF)=270 Hz), 71.0, 44.2, 35.9, 35.6, 27.1, 26.9, 25.1, 20.9. MS(API) m/z 555 (M+H)⁺.

Example 48 Assay for Human COX-1 and COX-2 Enzyme Activity in HumanWhole Blood

The assay for COX-1 and COX-2 enzyme activity, in the human whole bloodwas performed as described in Brideau et al., Inflamm Res., 45: 68-74(1996)). Human blood (50 mL) from male or female donors who had notreceived any aspirin or NSAIDs for 14 days was collected at two localarea blood donor centers and placed in polypropylene syringes containingsodium heparin (20 units per mL blood, final concentration). The bloodwas transported to the laboratory on ice packs and used within 1.5 hoursof collection. Upon receipt in the laboratory, the blood was allowed tocome to room temperature for 15 minutes prior to distribution in 1 mLaliquots per well of 24 well tissue culture plates. The plates were thenplaced on a gently rotating platform shaker in a 5% CO₂ incubator at 37°C. for 15 minutes. Test compounds were dissolved in DMSO, at 1000 foldthe final desired concentration, and further diluted, as indicated, inDMSO. One μL of each dilution of the test compound was added per well,in duplicate wells; wells not receiving test compound (e.g., basal,background or control wells) received 1 μL DMSO.

To induce COX-2, lipopolysaccharide (LPS) from E. coli (LPS, serotype026:B6 or serotype 0127:B8, Sigma Chemical Co., St. Louis, Mo.,Catalogue No. L3755 or L3129, respectively) was added at 10 μg/mL (2 μLof 5 mg/mL LPS in DMSO) to appropriate wells 15 minutes after theaddition of the test compound. (Basal or background wells not incubatedwith LPS received 2 μL of DMSO.) For the stimulation of COX-1, thecalcium ionophore, A23187 (free acid from Sigma Chemical Co., St. Louis,Mo., Catalogue No. C7522) was added at 25 μM (1 μL of 25 mM stock inDMSO) to separate wells 4.5 hours after the addition of the testcompound. (Again, basal, background or control wells not stimulated withA23187 received 1 μL of DMSO.) At 5 hours after the addition of the testcompound, all incubations were terminated by placement on ice and theaddition of 2 mM EGTA (100 μL of 20 mM EGTA, tetrasodium, in PBS(phosphate buffered saline) without Ca⁺⁺ and Mg⁺⁺, pH 7.2)). Theresulting solutions, were transferred by polyethylene transfer pipettesto 15 mL polypropylene centrifuge tubes and centrifuged at 1200 g for 10minutes at 4° C. One hundred μL of plasma was removed from each bloodsample and added to 1 mL of methanol in new 15 mL polypropylenecentrifuge tubes, vortexed, and stored overnight at −20° C. The nextday, the samples were centrifuged at 2000 g for 10 minutes at 4° C. andthe supernatants transferred to glass tubes and evaporated to dryness.The samples were assayed for thromboxane B₂ using EIA kits supplied byCayman Chemical Co. (Ann Arbor, Mich., Catalogue No. 519031) induplicate wells after reconstitution with EIA Buffer and appropriatedilution (2000 fold for COX-1 and 500 fold for Cox-2 samples).

The % inhibition for COX-1 and COX-2 enzyme activity in human wholeblood by the test compounds, at the indicated concentrations, are givenin Table 1.

TABLE 1 % INHIBITION OF COX-1 AND COX-2 ENZYME ACTIVITY IN HUMAN WHOLEBLOOD Test COX-1 Inhibition COX-2 Inhibition COX-2 Inhibition Compound(% at 100 μM) (% at 10 μM) (% at 1 μM) Example 1g 35 75 35 Example 1h 6090 50 Example 2c 40 25 10 Example 2d 35 90 60 Example 3e 0 90 60 Example3f 20 80 55 Example 4e 45 70 30 Example 4f 20 95 70 Example 5d 25 80 20Example 5e 55 85 50 Example 6e 40 85 50 Example 6f 80 95 50 Example 7d80 95 25 Example 7e 90 100 65 Example 8d 70 90 20 Example 8e 90 95 50Example 9d 40 85 30 Example 9e 45 100 60 Example 10d 100 100 25 Example10e 85 100 70 Example 11d 25 30 0 Example 11e 90 100 95 Example 11f 8590 55 Example 12d 0 45 15 Example 12e 55 95 70 Example 13d 0 25 25Example 13e 40 100 55 Example 14d 0 70 15 Example 14e 90 95 70 Example15d 10 40 0 Example 15e 35 75 35 Example 16b 10 55 20 Example 16c 10 8545 Example 17b 80 100 135 Example 17d 25 25 0 Example 18d 40 90 45Example 18e 80 95 55 Example 19b 40 100 20 Example 19c 35 30 20 Example20f 35 65 10 Example 20g 45 85 20 Example 21b 10 25 10 Example 21c 60 9045 Example 22c 40 80 25 Example 22d 75 30 30 Example 23d −20 10 0Example 23e 45 100 35 Example 24d 85 85 50 Example 24e 100 100 95Example 25e 10 0 15 Example 25f 55 40 40 Example 26a 25 85 50 Example26b 70 100 55 Example 27a 45 90 40 Example 27b 65 100 50 Example 28a 3055 30 Example 28b 55 80 40 Example 29a −15 65 35 Example 29b 0 60 0Example 31c 10 15 0 Example 32c −20 75 15 Example 32d 0 85 20 Example33a 75 100 40 Example 33b 85 100 90 Example 34a 95 100 90 Example 34b 75100 90 Example 35c 0 30 25 Example 36b 30 55 30 Example 36c 55 80 40Example 37b 50 90 35 Example 37c −15 20 20 Example 38c 10 25 15 Example39 100 100 85 Example 41 40 45 0 Example 42d 0 100 0 Example 42e 35 5510 Example 43g 30 10 0 Example 43h 50 20 10 Example 44d 10 60 30 Example44e 60 100 30 Example 47f 85 65 30The results show that the compounds in Table 1 have COX-2 selectivity.

Example 49 Rat Carrageenan Air-Pouch

The carrageenan air pouch model was performed as described by Sedgwicket al., Agents Actions 18, 429-438, (1986) and Masferrer et al., Proc.Natl. Acad. Sci. 91, 3228-3232 (1994). Air pouches were produced bysubcutaneous injection of 20 ml of sterile air on day (−6) into theintrascapular area of the back of the anesthesia rat (male CD, CharlesRiver, 175-200 g). An additional 10 mL of sterile air was injected intothe pouch 3 days later to keep the space open and to assist in thedevelopment of the interior membrane. Six days after the initial airinjection, 1 mL of a 1% solution of carrageenan (Sigma, lambda fraction)dissolved in pyrogen-free saline was injected directly into the pouch toproduce an inflammatory response. The test compound in vehicle (3mL/rat, 0.5% Methocel) was administered by oral intubation 1 hour priorto carrageenan injection into the inflammatory pouch. After 4 hours theexudate was removed by pipette into a calibrated centrifuge tube and thevolume measured. The number of leukocytes in the exudate was determinedby cell counting with a Beckman Coulter Particle Counter with the lowerthreshold set to exclude red blood cells. The exudate samples wereassayed without further processing for PGE₂ (prostaglandin E₂) usingPGE₂ EIA kit-Monoclonal, from Cayman Chemical Co. (Ann Arbor, Mich.,Catalogue No. 514010).

The % inhibition for the cell infiltration and the % inhibition for PGE₂by the test compounds, at the indicated concentrations, are given inTable 2.

TABLE 2 Cell Infiltration (% inhibition PGE-2 (% Inhibition TestCompound @ 45 μmol/kg) at @ 45 μmol/kg) Example 3f 42 45 Example 5e 1040 Example 13e 23 45 Example 24e 43 78

The compounds in Table 2 inhibit cell infiltration with an accompanyingdecrease in PGE₂ levels.

The disclosure of each patent, patent application and publication citedor described in the present specification is hereby incorporated byreference herein in its entirety.

Although the invention has been set forth in detail, one skilled in theart will appreciate that numerous changes and modifications can be madeto the invention, and that such changes and modifications can be madewithout departing from the spirit and scope of the invention.

1. A compound of Formula (I), (II) or a pharmaceutically acceptable saltthereof; wherein the compound of Formula (I) is:

wherein: R₁ is —S(O)₂—NH₂; R₁′ at each occurrence is independently ahydrogen, a halogen, a methyl or CH₂OH; R₂ is a substituted lower alkylgroup, a cycloalkyl group, an aryl group or a heteroaryl; R₃ is: (a)—(C(R₄)(R′₄))_(k)—Y—(C(R₄)(R′₄))_(n)—O—V; (b)—C(Z)-(C(R₄)(R′₄))_(k)—O—V; (c)—C(Z)-(C(R₄)(R′₄))_(k)—Y—(C(R₄)(R′₄))_(n)—O—V; (d)—(C(R₄)(R′₄))_(k)—Y—(C(R₄)(R′₄))_(n)—C(Z)-(C(R₄)(R′₄))_(n)—O—V; (e)—(C(R₄)(R′₄))_(k)—CH═CH—(C(R₄)(R′₄))_(p)—O—V; (g)—(C(R₄)(R′₄))_(n)—W-Q-(C(R₄)(R′₄))_(k)—O—V; (h)—C(Z)-W-Q-(C(R₄)(R′₄))_(k)—O—V; (i) —C(O)—N(R_(i))—O—(C(R₄)(R′₄)—O—V;(j) —(C(R₄)(R′₄))_(k)—C═C—(C(R₄)(R′₄))_(p)—O—V; (k)—(C(R₄)(R′₄))_(k)—Y—(C(R₄)(R′₄))_(k)—Y—(C(R₄)(R′₄))_(k)—O—V; (l)—(C(R₄)(R′₄))_(p)-E-N(R_(i))—O—W-Q-(C(R₄)(R′₄)_(k)—O—V; (m)—(C(R₄)(R′₄))_(p)-E-N(R_(i))—O—(C(R₄)(R′₄)_(k)—O—V; (n)—(C(R₄)(R′₄))_(p)—N(R_(i))—O—(C(R₄)(R′₄)_(k)—O—V;(o)—(C(R₄)(R′₄))_(p)—O—N(R_(i))—(C(R₄)(R′₄)_(k)—O—V; (p)—(C(R₄)(R′₄))_(p)—O—N(R_(i))-E-(C(R₄)(R′₄)_(k)—O—V; or (q) —(C(R₄)(R′4))_(p)—O—N(R_(i))-E-W-Q-(C(R₄)(R′₄)_(k)—O—V; R₄ and R′₄ at eachoccurrence are independently a hydrogen, a halogen, a lower alkyl group,or an alkoxy group; V is —NO, —NO₂, or a hydrogen; Y at each occurrenceis independently an oxygen, —S(O)_(o)— or —N(R_(a))R_(i)—; Z is an oxo,a thial, an oxime or a hydrazone; Q is Y or a covalent bond; W at eachoccurrence is independently an aryl group, an alkylaryl group, aheterocyclic ring or an alkylheterocyclic ring; E is —C(O) or —S(O)_(o);R_(a) is a lone pair of electron, a hydrogen or a lower alkyl group;R_(i) is a hydrogen, an alkyl, an aryl, an alkylcarboxylic acid, anarylcarboxylic acid, an alkylcarboxylic ester, an arylcarboxylic ester,an alkylcarboxamido, an arylcarboxamido, an alkylaryl, an alkylsulfinyl,an alkylsulfonyl, an arylsulfinyl, an arylsulfonyl, a sulfonamido, acarboxamido, a carboxylic ester, an aminoalkyl, an aminoaryl,—(C(R₄)(R′₄))_(n)—O—V, or —(N₂O₂—)⁻.M⁺, wherein M⁺ is an organic orinorganic cation; o is an integer from 0 to 2; k is an integer from 1 to6; p at each occurrence is independently an integer from 0 to 10; n ateach occurrence is independently an integer from 2 to 10; wherein thecompound of Formula (II) is:

wherein R₁, R₁′, R₂ and R₃ are as defined herein.
 2. A compositioncomprising the compound of claim 1 and a pharmaceutically acceptablecarrier.
 3. The composition of claim 2, further comprising at least onetherapeutic agent.
 4. The composition of claim 3, wherein thetherapeutic agent is a steroid, a nonsteroidal antiinflammatorycompound, a 5-lipoxygenase (5-LO) inhibitor, a leukotriene B₄ receptorantagonist, a leukotriene A₄ hydrolase inhibitor, a 5-HT agonist, a3-hydroxy-3-methylglutaryl coenzyme A inhibitor, a H₂ antagonist, anantineoplastic agent, an antiplatelet agent, a thrombin inhibitor, athromboxane inhibitor, a decongestant, a diuretic, a sedating ornon-sedating anti-histamine, an inducible nitric oxide synthaseinhibitor, an opioid, an analgesic, a Helicobacter pylori inhibitor, aproton pump inhibitor, an isoprostane inhibitor, or a mixture of two ormore thereof.
 5. The composition of claim 4, wherein the nonsteroidalantiinflammatory compound is acetaminophen, aspirin, diclofenac,ibuprofen, ketoprofen or naproxen.
 6. A composition comprising at leastone compound of claim 1 and at least one compound that donates,transfers or releases nitric oxide, or induces the production ofendogenous nitric oxide or endothelium-derived relaxing factor, or is asubstrate for nitric oxide synthase.
 7. The composition of claim 6,further comprising a pharmaceutically acceptable carrier.
 8. Thecomposition of claim 6, wherein the compound that donates, transfers, orreleases nitric oxide, or induces the production of endogenous nitricoxide or endothelium-derived relaxing factor or is a substrate fornitric oxide synthase is an S-nitrosothiol.
 9. The composition of claim8, wherein the S-nitrosothiol is S-nitroso-N-acetylcysteine,S-nitroso-captopril, S-nitroso-N-acetylpenicillamine,S-nitroso-homocysteine, S-nitroso-cysteine, S-nitroso-glutathione, orS-nitroso-cysteinyl-glycine.
 10. The composition of claim 8, wherein theS-nitrosothiol is: (i) HS(C(R_(e))(R_(f)))_(m)SNO; (ii)ONS(C(R_(e))(R_(f)))_(m)R_(e); or (iii)H₂N—CH(CO₂H)—(CH₂)_(m)—C(O)NH—CH(CH₂SNO)—C(O)NH—CH₂—CO₂H; wherein m isan integer from 2 to 20; R_(e) and R_(f) are each independently ahydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy, anhydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring. acycloalkylalkyl, a heterocyclicalkyl, an alkoxy, a haloalkoxy, an amino,an alkylamino, a dialkylamino, an arylamino, a diarylamino, analkylarylamino, an alkoxyhaloalkyl, a haloalkoxy, a sulfonic acid, asulfonic ester, an alkylsulfonic acid, an arylsulfonic acid, anarylalkoxy, an alkylthio, an arylthio, a cyano, an aminoalkyl, anaminoaryl, an aryl, an arylalkyl, a carboxamido, a alkylcarboxamido, anarylcarboxamido, an amidyl, a carboxyl, a carbamoyl, an alkylcarboxylicacid, an arylcarboxylic acid, an alkylcarbonyl, an arylcarbonyl, anester, a carboxylic ester, an alkylcarboxylic ester, an arylcarboxylicester, a haloalkoxy, a sulfonamido, an alkylsulfonamido, anarylsulfonamido, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfonyl,an arylsulfonyloxy, a urea, a nitro, or -T-Q-, or R_(e) and R_(f) takentogether are an oxo, a thial, a heterocyclic ring, a cycloalkyl group,an oxime, a hydrazone or a bridged cycloalkyl group; Q is —NO or —NO₂;and T is independently a covalent bond, a carbonyl, an oxygen,—S(O)_(o)— or —N(R_(a))R_(i)—, wherein o is an integer from 0 to 2,R_(a) is a lone pair of electrons, a hydrogen or an alkyl group; R_(i)is a hydrogen, an alkyl, an aryl, an alkylcarboxylic acid, anarylcarboxylic acid, an alkylcarboxylic ester, an arylcarboxylic ester,an alkylcarboxamido, an arylcarboxamido, an alkylsulfinyl, analkylsulfonyl, an alkylsulfonyloxy, an arylsulfinyl, an arylsulfonyloxy,an arylsulfonyl, a sulfonamido, a carboxamido, a carboxylic ester, anaminoalkyl, an aminoaryl, or —(N₂O₂—)⁻.M⁺, wherein M⁺ is an organic orinorganic cation; with the proviso that when R_(i) is —(N₂O₂—)⁻.M⁺, then“-T-Q” can be a hydrogen, an alkyl group, an alkoxyalkyl group, anaminoalkyl group, a hydroxy group or an aryl group.
 11. The compositionof claim 6, wherein the compound that donates, transfers, or releasesnitric oxide, or induces the production of endogenous nitric oxide orendothelium-derived relaxing factor, or is a substrate for nitric oxidesynthase is L-arginine, L-homoarginine, N-hydroxy-L-arginine, nitrosatedL-arginine, nitrosylated L-arginine, nitrosated N-hydroxy-L-arginine,nitrosylated N-hydroxy-L-arginine, nitrosated L-homoarginine,nitrosylated L-homoarginine), citrulline, ornithine, glutamine, lysine,an arginase inhibitor or a nitric oxide mediator.
 12. The composition ofclaim 6, wherein the compound that donates, transfers, or releasesnitric oxide, or induces the production of endogenous nitric oxide orendothelium-derived relaxing factor, or is a substrate for nitric oxidesynthase is: (i) a compound that comprises at least one ON—O— or ON—N—group; (ii) a compound that comprises at least one O₂N—O—, O₂N—N— orO₂N—S— or group; (iii) a N-oxo-N-nitrosoamine having the formula:R^(1″)R^(2″)N—N(O-M⁺)—NO, wherein R^(1″) and R^(2″) are eachindependently a polypeptide, an amino acid, a sugar, an oligonucleotide,a straight or branched, saturated or unsaturated, aliphatic or aromatic,substituted or unsubstituted hydrocarbon, or a heterocyclic group, andM⁺ is an organic or inorganic cation.
 13. The composition of claim 6,further comprising at least one therapeutic agent.
 14. The compositionof claim 13, wherein the therapeutic agent is a steroid, a nonsteroidalantiinflammatory compound, a 5-lipoxygenase (5-LO) inhibitor, aleukotriene B₄ receptor antagonist, a leukotriene A₄ hydrolaseinhibitor, a 5-HT agonist, a HMG CoA inhibitor, a H₂ antagonist, anantineoplastic agent, an antiplatelet agent, a thrombin inhibitor, athromboxane inhibitor, a decongestant, a diuretic, a sedating ornon-sedating anti-histamine, an inducible nitric oxide synthaseinhibitor, an opioid, an analgesic, a Helicobacter pylori inhibitor, aproton pump inhibitor, an isoprostane inhibitor, or a mixture of two ormore thereof.
 15. The composition of claim 14, wherein the nonsteroidalantiinflammatory compound is acetaminophen, aspirin, diclofenac,ibuprofen, ketoprofen or naproxen.
 16. A kit comprising at least onecompound of claim
 1. 17. The kit of claim 16, further comprising (i) atleast one compound that donates, transfers or releases nitric oxide,induces the production of endogenous nitric oxide or endothelium-derivedrelaxing factor, or is a substrate for nitric oxide synthase; (ii) atleast one therapeutic agent; or (iii) at least one compound thatdonates, transfers or releases nitric oxide, induces the production ofendogenous nitric oxide or endothelium-derived relaxing factor, or is asubstrate for nitric oxide synthase and at least one therapeutic agent.18. The kit of claim 17, wherein the at least one compound that donates,transfers or releases nitric oxide, induces the production of endogenousnitric oxide or endothelium-derived relaxing factor, or is a substratefor nitric oxide synthase; the at least one therapeutic agent; or the atleast one compound that donates, transfers or releases nitric oxide,induces the production of endogenous nitric oxide or endothelium-derivedrelaxing factor, or is a substrate for nitric oxide synthase and atleast one therapeutic agent; are in the form of separate components inthe kit. 19.4-(5-(4-Methylphenyl)-3-((3-(nitrooxy)propoxy)methyl)pyrazolyl)-benzenesulfonamide;4-(1-cyclohexyl-3-(4-(nitrooxy)butanoyl)pyrazol-5-yl)benzenesulfonamide;4-(5-(4-chlorophenyl)-3-((3-(nitrooxy)propoxy)methyl)pyrazolyl)benzenesulfonamide;4-(3-((3-(nitrooxy)propoxy)methyl)-5-phenylpyrazolyl)benzenesulfonamide;or a pharmaceutically acceptable salt thereof.
 20. A compositioncomprising at least one compound of claim 19 and a pharmaceuticallyacceptable carrier.
 21. The composition of claim 20, further comprising(i) at least one compound that donates, transfers or releases nitricoxide, induces the production of endogenous nitric oxide orendothelium-derived relaxing factor, or is a substrate for nitric oxidesynthase; (ii) at least one therapeutic agent; or (iii) at least onecompound that donates, transfers or releases nitric oxide, induces theproduction of endogenous nitric oxide or endothelium-derived relaxingfactor, or is a substrate for nitric oxide synthase and at least onetherapeutic agent.
 22. A kit comprising at least one compound of claim19.